U.S. patent number 8,440,660 [Application Number 13/135,790] was granted by the patent office on 2013-05-14 for method for treating a disease related to the glucocorticoid receptor.
This patent grant is currently assigned to Santen Pharmaceutical Co., Ltd.. The grantee listed for this patent is Masatomo Kato, Sachiko Kobayashi, Mamoru Matsuda, Toshiyuki Mori, Masato Nagatsuka, Miwa Takai. Invention is credited to Masatomo Kato, Sachiko Kobayashi, Mamoru Matsuda, Toshiyuki Mori, Masato Nagatsuka, Miwa Takai.
United States Patent |
8,440,660 |
Matsuda , et al. |
May 14, 2013 |
Method for treating a disease related to the glucocorticoid
receptor
Abstract
A method for treating a disease related to the glucocorticoid
receptor involving administering a pharmacologically effective
amount of a 1,2-hydroquinoline compound.
Inventors: |
Matsuda; Mamoru (Ikoma,
JP), Nagatsuka; Masato (Ikoma, JP), Mori;
Toshiyuki (Ikoma, JP), Kobayashi; Sachiko (Ikoma,
JP), Kato; Masatomo (Ikoma, JP), Takai;
Miwa (Ikoma, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Matsuda; Mamoru
Nagatsuka; Masato
Mori; Toshiyuki
Kobayashi; Sachiko
Kato; Masatomo
Takai; Miwa |
Ikoma
Ikoma
Ikoma
Ikoma
Ikoma
Ikoma |
N/A
N/A
N/A
N/A
N/A
N/A |
JP
JP
JP
JP
JP
JP |
|
|
Assignee: |
Santen Pharmaceutical Co., Ltd.
(Osaka, JP)
|
Family
ID: |
39401671 |
Appl.
No.: |
13/135,790 |
Filed: |
July 14, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20110275620 A1 |
Nov 10, 2011 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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12312392 |
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8008496 |
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PCT/JP2007/072081 |
Nov 14, 2007 |
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Foreign Application Priority Data
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Nov 14, 2006 [JP] |
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2006-307651 |
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Current U.S.
Class: |
514/230.5;
514/314; 514/311 |
Current CPC
Class: |
A61P
3/08 (20180101); A61P 25/28 (20180101); A61P
5/44 (20180101); A61P 5/00 (20180101); A61P
43/00 (20180101); C07D 409/12 (20130101); A61P
3/06 (20180101); A61P 11/00 (20180101); C07D
405/12 (20130101); A61P 9/10 (20180101); A61P
25/18 (20180101); A61P 25/30 (20180101); A61P
25/00 (20180101); A61P 37/02 (20180101); A61P
3/04 (20180101); A61P 27/02 (20180101); A61P
27/06 (20180101); A61P 37/00 (20180101); C07D
401/12 (20130101); A61P 29/00 (20180101); A61P
3/10 (20180101); A61P 3/14 (20180101); A61P
9/00 (20180101); C07D 409/14 (20130101); A61P
37/08 (20180101); A61P 3/12 (20180101); C07D
417/12 (20130101); A61P 11/02 (20180101); A61P
9/12 (20180101); A61P 1/04 (20180101); A61P
37/06 (20180101); A61P 17/00 (20180101); C07D
215/14 (20130101); A61P 11/06 (20180101); A61P
3/00 (20180101) |
Current International
Class: |
A61K
31/535 (20060101); A61K 31/47 (20060101) |
Field of
Search: |
;514/230.5,311,314 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1 944 290 |
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Jul 2008 |
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EP |
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10-510840 |
|
Oct 1998 |
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JP |
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2002-193955 |
|
Jul 2002 |
|
JP |
|
WO 96/19458 |
|
Jun 1996 |
|
WO |
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WO 96/19458 |
|
Jun 1996 |
|
WO |
|
WO 2006/019716 |
|
Feb 2006 |
|
WO |
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WO 2007/032556 |
|
Mar 2007 |
|
WO |
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WO 2008/111632 |
|
Sep 2008 |
|
WO |
|
Other References
Hajime Nawata, Sougou Rinsyou, "New horizon of glucocorticoid
therapy in 21st century," 54(7), 1951-2076 (2005). cited by
applicant .
Ku, Yi-Yin; Grieme, Tim; Raje, Prasad; Sharma, Padam; King, Steve;
Morton, Edward: "Asymmetric Synthesis of A-240610.0 via a New
Atropselective Approach for Axially Chiral Biaryls with Chirality
Transfer," Journal of the American Chemical Society, vol. 124,
2002, pp. 4282-4286. cited by applicant .
Supplementary European Search Report dated Nov. 4, 2010 in European
application No. EP 07 83 1811. cited by applicant .
International Search Report for PCT/JP2007/072081 dated Jan. 29,
2008. cited by applicant.
|
Primary Examiner: Weddington; Kevin E
Attorney, Agent or Firm: Holtz Holtz Goodman & Chick
P.C.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation application of application Ser.
No. 12/312,392 filed May 7, 2009 (U.S. Pat. No. 8,008,496), which
is the United States national phase application under 35 USC 371 of
International application PCT/JP2007/072081 filed Nov. 14, 2007.
The entire contents of each of application Ser. No. 12/312,392 and
International application PCT/JP2007/072081 are hereby incorporated
by reference herein.
Claims
The invention claimed is:
1. A method for treating a disease related to the glucocorticoid
receptor selected from the group consisting of obesity, enteritis,
asthma, atopic dermatitis, allergic rhinitis, Alzheimer's disease,
hypertension, hypercalcemia, hyperinsulinemia, hyperlipidemia, a
homeostasis-related disease causing an abnormality of
neuro-immune-endocrine balance and glaucoma, the method comprising
administering a pharmacologically effective amount of a compound
represented by the following formula (1) or a pharmaceutically
acceptable salt thereof as an active ingredient to a patient:
##STR00236## wherein R.sup.1 represents a hydrogen atom or a lower
alkyl group; R.sup.2 represents a hydrogen atom or a lower alkyl
group; R.sup.3 and R.sup.4 are the same or different and represent
a hydrogen atom or a lower alkyl group; R.sup.5 represents a
hydrogen atom or a lower alkyl group; R.sup.6 represents a halogen
atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a
nitro group or a cyano group; X represents --C(O)--,
--C(O)NR.sup.8--, --S(O)-- or --S(O).sub.2--; R.sup.7 and/or
R.sup.8 are the same or different and represent a hydrogen atom, a
lower alkyl group which optionally has a substituent, a lower
alkenyl group which optionally has a substituent, a lower alkynyl
group which optionally has a substituent, a lower cycloalkyl group
which optionally has a substituent, an aryl group which optionally
has a substituent, a heterocyclic group which optionally has a
substituent, a lower alkoxy group which optionally has a
substituent, a lower alkenyloxy group which optionally has a
substituent, a lower alkynyloxy group which optionally has a
substituent, a lower cycloalkyloxy group which optionally has a
substituent, an aryloxy group which optionally has a substituent or
a heterocyclic oxy group which optionally has a substituent; Y
represents a lower alkylene group; Z represents a chalcogen atom; p
represents 0, 1, 2 or 3, in the case where p is 2 or 3, each
R.sup.6 are the same or different.
2. The method according to claim 1, wherein in the formula (1),
R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2
represents a hydrogen atom or a lower alkyl group; R.sup.3 and
R.sup.4 are the same or different and represent a hydrogen atom or
a lower alkyl group; R.sup.5 represents a hydrogen atom or a lower
alkyl group; R.sup.6 represents a halogen atom, a lower alkyl
group, a hydroxy group, a lower alkoxy group, a nitro group or a
cyano group; X represents --CO--, --C(O)NR.sup.8--, --S(O)-- or
--S(O).sub.2--; R.sup.7 and/or R.sup.8 are the same or different
and represent a hydrogen atom, a lower alkyl group, a lower alkenyl
group, a lower alkynyl group, a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower alkoxy group, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy
group, an aryloxy group or a heterocyclic oxy group; in the case
where R.sup.7 and/or R.sup.8 is a lower alkyl group, a lower
alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower
alkenyloxy group or a lower alkynyloxy group, the lower alkyl
group, the lower alkenyl group, the lower alkynyl group, the lower
alkoxy group, the lower alkenyloxy group or the lower alkynyloxy
group optionally has one or a plurality of substituents selected
from the group consisting of a halogen atom, a lower cycloalkyl
group, an aryl group, a heterocyclic group, a hydroxy group, a
lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy
group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group and --NR.sup.aR.sup.b; in the case where
R.sup.7 and/or R.sup.8 is a lower cycloalkyl group, an aryl group,
a heterocyclic group, a lower cycloalkyloxy group, an aryloxy group
or a heterocyclic oxy group, the lower cycloalkyl group, the aryl
group, the heterocyclic group, the lower cycloalkyloxy group, the
aryloxy group or the heterocyclic oxy group optionally has one or a
plurality of substituents selected from the group consisting of a
halogen atom, a lower alkyl group, a halogenated lower alkyl group,
an aryl group, lower alkenyl group, a lower alkynyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy
group, a lower alkoxy group, a halogenated lower alkoxy group, a
lower alkenyloxy group, a lower alkynyloxy group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
mercapto group, a lower alkyl thio group, a lower alkenylthio
group, a lower alkynylthio group, a lower cycloalkylthio group, an
arylthio group, a heterocyclic thio group, a lower alkylcarbonyl
group, an arylcarbonyl group, a lower alkoxycarbonyl group, an
aryloxycarbonyl group, a lower alkylcarbonyloxy group, an
arylcarbonyloxy group, --NR.sup.aR.sup.b, a nitro group and a cyano
group; R.sup.a and R.sup.b are the same or different and represent
a hydrogen atom, a lower alkyl group, a lower alkenyl group, a
lower alkynyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxycarbonyl group or an
aryloxycarbonyl group; Y represents a lower alkylene group; Z
represents a chalcogen atom; p represents 0, 1, 2 or 3, in the case
where p is 2 or 3, each R.sup.6 is the same or different.
3. The method according to claim 1, wherein in the formula (1),
R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2
represents a hydrogen atom or a lower alkyl group; R.sup.3 and
R.sup.4 are the same or different and represent a hydrogen atom or
a lower alkyl group; R.sup.5 represents a hydrogen atom or a lower
alkyl group; R.sup.6 represents a halogen atom, a lower alkyl
group, a hydroxy group, a lower alkoxy group or a nitro group; X
represents --CO--, --C(O)NR.sup.8--, --S(O)-- or --S(O).sub.2--;
R.sup.7 and/or R.sup.8 are the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxy group, a lower alkenyloxy group,
a lower alkynyloxy group, a lower cycloalkyloxy group, an aryloxy
group or a heterocyclic oxy group; in the case where R.sup.7 and/or
R.sup.8 is a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower alkoxy group, a lower alkenyloxy group or a
lower alkynyloxy group, the lower alkyl group, the lower alkenyl
group, the lower alkynyl group, the lower alkoxy group, the lower
alkenyloxy group or the lower alkynyloxy group optionally has one
or a plurality of substituents selected from the group consisting
of a halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, a lower alkoxy group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group and
--NR.sup.aR.sup.b; in the case where R.sup.7 and/or R.sup.8 is a
lower cycloalkyl group, an aryl group, a heterocyclic group, a
lower cycloalkyloxy group, an aryloxy group or a heterocyclic oxy
group, the lower cycloalkyl group, the aryl group, the heterocyclic
group, the lower cycloalkyloxy group, the aryloxy group or the
heterocyclic oxy group optionally has one or a plurality of
substituents selected from the group consisting of a halogen atom,
a lower alkyl group, a halogenated lower alkyl group, a lower
cycloalkyl group, an aryl group, a hydroxy group, a lower alkoxy
group, a halogenated lower alkoxy group, a cycloalkyloxy group, an
aryloxy group, a mercapto group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group,
a lower alkylcarbonyl group, an arylcarbonyl group, a lower
alkoxycarbonyl group, an aryloxycarbonyl group, a lower
alkylcarbonyloxy group, an arylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group; R.sup.a and
R.sup.b are the same or different and represent a hydrogen atom, a
lower alkyl group or a lower alkoxycarbonyl group; Y represents a
lower alkylene group; Z represents an oxygen atom or a sulfur atom;
p represents 0, 1, 2 or 3, in the case where p is 2 or 3, each
R.sup.6 is the same or different.
4. The method according to claim 1, wherein in the formula (1),
R.sup.1 represents a lower alkyl group; R.sup.2 represents a
hydrogen atom; R.sup.3 and R.sup.4 represent a lower alkyl group;
R.sup.5 represents a lower alkyl group; R.sup.6 represents a
halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy
group or a nitro group; X represents --CO--, --C(O)NR.sup.8-- or
--S(O).sub.2--; R.sup.7 represents a lower alkyl group, a lower
alkenyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxy group or an aryloxy group; in
the case where R.sup.7 is a lower alkyl group or a lower alkoxy
group, the lower alkyl group or the lower alkoxy group optionally
has one or a plurality of substituents selected from the group
consisting of a halogen atom, an aryl group, a heterocyclic group,
a lower alkoxy group and --NR.sup.aR.sup.b; in the case where
R.sup.7 is an aryl group, a heterocyclic group or an aryloxy group,
the aryl group, the heterocyclic group or the aryloxy group
optionally has one or a plurality of substituents selected from the
group consisting of a halogen atom, a lower alkyl group, a
halogenated lower alkyl group, an aryl group, a hydroxy group, a
lower alkoxy group, a halogenated lower alkoxy group, a lower
alkylthio group, a lower alkylcarbonyl group, a lower
alkoxycarbonyl group, a lower alkylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group; R.sup.a and
R.sup.b are the same or different and represent a hydrogen atom, a
lower alkyl group or a lower alkoxycarbonyl group; R.sup.8
represents a hydrogen atom or a lower alkyl group; in the case
where R.sup.8 is a lower alkyl group, the lower alkyl group
optionally has one or a plurality of substituents selected from the
group consisting of an aryl group or a heterocyclic group; Y
represents a lower alkylene group; Z represents an oxygen atom; p
represents 0, 1 or 2, in the case where p is 2, each R.sup.6 is the
same or different.
5. The method according to claim 1, wherein in the formula (1),
R.sup.1 represents a lower alkyl group; R.sup.2 represents a
hydrogen atom; R.sup.3 and R.sup.4 represent a lower alkyl group;
R.sup.5 represents a lower alkyl group; R.sup.6 represents a
halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy
group or a nitro group; X represents --CO--, --C(O)NR.sup.8-- or
--S(O).sub.2--; R.sup.7 represents a lower alkyl group, a lower
alkenyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxy group or an aryloxy group; in
the case where R.sup.7 is a lower alkyl group, the lower alkyl
group optionally has one or a plurality of substituents selected
from the group consisting of a halogen atom, an aryl group, a
heterocyclic group, a lower alkoxy group and --NR.sup.aR.sup.b; in
the case where R.sup.7 is an aryl group, the aryl group optionally
has one or a plurality of substituents selected from the group
consisting of a halogen atom, a lower alkyl group, a halogenated
lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy
group, a lower alkylthio group, a lower alkylcarbonyl group, a
lower alkoxycarbonyl group, a lower alkylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group; in the case
where R.sup.7 is a heterocyclic group, the heterocyclic group
optionally has one or a plurality of substituents selected from the
group consisting of a halogen atom, a lower alkyl group, an aryl
group, a hydroxy group, a lower alkoxy group, a lower alkylthio
group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group
and a nitro group; in the case where R.sup.7 is a lower alkoxy
group, the lower alkoxy group optionally has one or a plurality of
substituents selected from the group consisting of a halogen atom
and an aryl group; in the case where R.sup.7 is an aryloxy group,
the aryloxy group optionally has one or a plurality of substituents
selected from the group consisting of a halogen atom and a lower
alkoxy group; R.sup.a and R.sup.b are the same or different and
represent a hydrogen atom, a lower alkyl group or a lower
alkoxycarbonyl group; R.sup.8 represents a hydrogen atom or a lower
alkyl group; in the case where R.sup.8 is a lower alkyl group, the
lower alkyl group optionally has one or a plurality of substituents
selected from the group consisting of an aryl group or a
heterocyclic group; Y represents a lower alkylene group; Z
represents an oxygen atom; p represents 0, 1 or 2, in the case
where p is 2, each R.sup.6 is the same or different.
6. The method according to claim 1, wherein in the formula (1), Z
represents an oxygen atom.
7. The method according to claim 1, wherein in the formula (1),
R.sup.1, R.sup.3, R.sup.4 and R.sup.5 represent a methyl group;
R.sup.2 represents a hydrogen atom; and Y represents a methylene
group.
8. The method according to claim 1, wherein the compound is
selected from the group consisting of
6-(4-benzoyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-
-trimethyl-1,2-dihydroquinoline,
6-(4-t-butoxycarbonylaminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylph-
enoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-cyclohexylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-3-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-butyryloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-
-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-propionyloxyphenyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
6-(4-acryloyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,-
4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiophen-3-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[4-(furan-2-ylcarbonyloxy)-2-methoxy-
phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(4-isobutyryloxy-2-methoxyphenyl)-2,-
2,4-trimethyl-1,2-dihydroquinoline,
(5-fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-phenylacetoxyphenyl)-2,2,-
4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-propionyloxyphenyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiophen-2-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-phenylpropionyloxy)p-
henyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[4-(furan-3-ylcarbonyloxy)-2-methoxy-
phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-2-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-nitrobenzoyloxy)phen-
yl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-(pyridin-2-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-(pyridin-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-acetoxybenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(1-t-butoxycarbonylpiperidin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5--
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methylthiobenzoyloxy-
)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(1-t-butoxycarbonylimidazol-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-f-
luoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-5-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(oxazol-4-ylcarbonyloxy-
)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(3-acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(3-fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-methylfuran-2-ylcarb-
onyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-3-ylacetoxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(4-acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxycarbonylbenzo-
yloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(6-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methylfuran-2-ylcarb-
onyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-t-butylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethy-
l)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyrimidin-5-ylcarbonyl-
oxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-nitrofuran-2-ylcarbo-
nyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-chloropyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-met-
hylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[4-(3-fluoropyridin-4-ylcarbonyloxy)-
-2-methoxyphenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-methyl-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(pyridin-3-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nitrophenox-
ymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(furan-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-5-(2-methoxy-5-ni-
trophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-methoxy-5-nitrophenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(2-methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-(thiophen-3-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(furan-3-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nit-
rophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxypyridin-3-ylc-
arbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-aminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-propylsulfonyloxyphenyl-
)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-ethylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(4-isopropylsulfonyloxy-2-methoxyphe-
nyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-butylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(2-methoxy-5-nitrophenoxymethyl)-6-(2-methoxy-4-propylsulfonyloxyphenyl-
)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methoxy-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-isopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methoxy-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-ethylsulfonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxymethyl)--
2,2,4-trimethyl-1,2-dihydroquinoline,
6-(2-methoxy-4-propylsulfonyloxyphenyl)-5-(2-methyl-5-nitrophenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-isopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxymeth-
yl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-(4-isobutylsulfonyloxy-2-methoxyphen-
yl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3,3,3-trifluoropropyls-
ulfonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxyphenoxycarbon-
yloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-chlorophenylaminocarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-meth-
ylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxyphenylaminoca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxyphenylaminoca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxycarbonylpheny-
laminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenox-
ymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(4-cyanophenylaminocarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methy-
lphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(morpholin-4-ylcarbonyl-
oxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-isopropylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylpheno-
xymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-methoxy-5-nitrophe-
noxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nitrophen-
oxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxy-
methyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-[N-benzyl-N-(2-dimethylaminoethyl)aminocarbonyloxy]-2-methoxyphenyl]-
-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-[N-(2-dimethylaminoethyl)-N-(pyridin-3-ylmethyl)aminocarbonyloxy]-2--
methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihy-
droquinoline, and
6-[4-[N-(2-dimethylaminoethyl)-N-ethylaminocarbonyloxy]-2-methoxyphenyl]--
5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
or a pharmaceutically acceptable salt thereof.
9. The method according to claim 1, wherein the glucocorticoid
receptor-related disease is glaucoma.
Description
TECHNICAL FIELD
The present invention relates to novel 1,2-dihydroquinoline
derivatives having substituted phenylchalcogeno lower alkyl group
and ester-introduced phenyl group as substituents or a salt
thereof, which are useful as pharmaceuticals. The derivatives have
a glucocorticoid receptor binding activity and are useful as
glucocorticoid receptor modulators having a nonsteroidal structure
(glucocorticoid receptor agonists and/or glucocorticoid receptor
antagonists).
BACKGROUND ART
A glucocorticoid receptor is a 94 kDa ligand-activated
intracellular transcriptional regulatory factor that is a member of
the nuclear receptor superfamily. This receptor is known to affect
the regulation of the metabolism of carbohydrates, proteins, fats
and the like, suppression of the immune or inflammatory responses,
activation of the central nervous system, regulation of
cardiovascular function, and basal and stress-related homeostasis
and the like due to its transcriptional regulatory action. As
diseases which are considered to be related to glucocorticoid
receptor, metabolic disorders such as diabetes and obesity,
inflammatory diseases such as enteritis and chronic obstructive
pulmonary diseases, autoimmune diseases such as connective tissue
diseases, allergic diseases such as asthma, atopic dermatitis and
allergic rhinitis, central nervous system diseases such as
psychiatric disorders, Alzheimer's disease and drug use disorders,
cardiovascular diseases such as hypertension, hypercalcemia,
hyperinsulinemia and hyperlipidemia, homeostasis-related diseases
causing an abnormality of neuro-immune-endocrine balance, glaucoma
and the like are known (SOUGOU RINSYOU, 54(7), 1951-2076 (2005),
JP-A-2002-193955). Therefore, a compound having a glucocorticoid
receptor binding activity is useful as a preventive and/or
therapeutic agent for these diseases.
As such a compound having a glucocorticoid receptor binding
activity, glucocorticoid receptor agonists synthesized in the
living body such as cortisol and corticosterone, synthetic
glucocorticoid receptor agonists such as dexamethasone, prednisone
and prednisilone, non-selective glucocorticoid receptor antagonists
such as RU486 and the like are known (JP-A-2002-193955).
On the other hand, compounds having a 1,2-dihydroquinoline
structure are disclosed as steroid receptor modulators in WO
2004/018429, JP-T-10-0510840, WO 2006/019716 and the like. In WO
2004/018429, JP-T-10-0510840 and WO 2006/019716, many compounds
which have very broad and a variety of chemical structures are
disclosed, and 1,2-dihydroquinoline structure is disclosed as one
of them. However, 1,2-dihydroquinoline derivatives having
substituted phenylchalcogeno lower alkyl group and ester-introduced
phenyl group as substituents have not been specifically disclosed
at all.
DISCLOSURE OF THE INVENTION
Problems to be Solved
It is a very interesting subject to study the synthesis of novel
1,2-dihydroquinoline derivatives having substituted
phenylchalcogeno lower alkyl group and ester-introduced phenyl
group as substituents or a salt thereof, and to find a
pharmacological action of the derivatives or a salt thereof.
Means of Solving Problems
The present inventors conducted the studies of the synthesis of
novel 1,2-dihydroquinoline derivatives having substituted
phenylchalcogeno lower alkyl group and ester-introduced phenyl
group as substituents or a salt thereof having a novel chemical
structure, and succeeded in producing a large number of novel
compounds.
These novel compounds have chemical structural features 1) to 3)
shown in below.
1) Having an ester structure (X is --C(O)--, --C(O)NR.sup.8--,
--S(O)-- or --S(O).sub.2--) in A part of the general formula
(1).
2) Having a hydroxy group or a lower alkoxy group in B part of the
general formula (1).
3) Having a substituted phenylchalcogeno lower alkyl group (Z is a
chalcogen atom, that is an oxygen atom, a sulfur atom or the like,
Y is a lower alkylene group) in C part of the general formula
(1).
##STR00001##
Further, as a result of the study about the pharmacological actions
of the novel compounds, the present inventors found that the novel
compounds have a glucocorticoid receptor binding activity and are
useful as pharmaceuticals, and thus the present invention has been
completed.
That is, the present invention relates to compounds represented by
the following general formula (1) or a salt thereof (hereinafter
referred to as "the present compound") and a pharmaceutical
composition containing the same. Further, a preferred invention in
its pharmaceutical use relates to glucocorticoid receptor
modulators, and its target diseases are considered to be
glucocorticoid receptor-related diseases, that is, metabolic
disorders such as diabetes and obesity, inflammatory diseases such
as enteritis and chronic obstructive pulmonary diseases, autoimmune
diseases such as connective tissue diseases, allergic diseases such
as asthma, atopic dermatitis and allergic rhinitis, central nervous
system diseases such as psychiatric disorders, Alzheimer's disease
and drug use disorders, cardiovascular diseases such as
hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma and the like, and an
invention relating to a preventive or a therapeutic agent for these
diseases is particularly preferred.
##STR00002##
[R.sup.1 represents a hydrogen atom or a lower alkyl group;
R.sup.2 represents a hydrogen atom or a lower alkyl group;
R.sup.3 and R.sup.4 may be the same or different and represent a
hydrogen atom or a lower alkyl group;
R.sup.5 represents a hydrogen atom or a lower alkyl group;
R.sup.6 represents a halogen atom, a lower alkyl group, a hydroxy
group, a lower alkoxy group, a nitro group or a cyano group;
X represents --C(O)--, --C(O)NR.sup.8--, --S(O)-- or
--S(O).sub.2--;
R.sup.7 and/or R.sup.8 may be the same or different and represent a
hydrogen atom, a lower alkyl group which may have a substituent, a
lower alkenyl group which may have a substituent, a lower alkynyl
group which may have a substituent, a lower cycloalkyl group which
may have a substituent, an aryl group which may have a substituent,
a heterocyclic group which may have a substituent, a lower alkoxy
group which may have a substituent, a lower alkenyloxy group which
may have a substituent, a lower alkynyloxy group which may have a
substituent, a lower cycloalkyloxy group which may have a
substituent, an aryloxy group which may have a substituent or a
heterocyclic oxy group which may have a substituent;
Y represents a lower alkylene group;
Z represents a chalcogen atom;
p represents 0, 1, 2 or 3, in the case where p is 2 or 3, each
R.sup.6 may be the same or different. Hereinafter the same shall
apply.]
Advantage of the Invention
The present invention provides novel 1,2-dihydroquinoline
derivatives having substituted phenylchalcogeno lower alkyl group
and ester-introduced phenyl group as substituents or a salt, which
are useful as pharmaceuticals. The present compound has an
excellent glucocorticoid receptor binding activity and is useful as
a glucocorticoid receptor modulator. In particular, the present
compound is useful as a preventive or therapeutic agent for
glucocorticoid receptor-related diseases, that is, metabolic
disorders such as diabetes and obesity, inflammatory diseases such
as enteritis and chronic obstructive pulmonary diseases, autoimmune
diseases such as connective tissue diseases, allergic diseases such
as asthma, atopic dermatitis and allergic rhinitis, central nervous
system diseases such as psychiatric disorders, Alzheimer's disease
and drug use disorders, cardiovascular diseases such as
hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma and the like.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, definitions of terms and phrases (atoms, groups and
the like) used in this specification will be described in detail.
In addition, when the definition of terms and phrases is applied to
the definition of another terms and phrases, a desirable range and
the particularly desirable range of each definition is also
applied.
The "chalcogen atom" refers to a oxygen or sulfur atom.
The "halogen atom" refers to a fluorine, chlorine, bromine or
iodine atom.
The "lower alkyl group" refers to a straight chain or branched
alkyl group having 1 to 8 carbon atoms, preferably 1 to 6,
especially preferably 1 to 4. Specific examples thereof include
methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,
n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl and isopentyl
groups and the like.
The "lower alkenyl group" refers to a straight chain or branched
alkenyl group having 2 to 8 carbon atoms, preferably 2 to 6,
especially preferably 2 to 4. Specific examples thereof include
vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,
isopropenyl, 2-methyl-1-propenyl and 2-methyl-2-butenyl groups and
the like.
The "lower alkynyl group" refers to a straight chain or branched
alkynyl group having 2 to 8 carbon atoms, preferably 2 to 6,
especially preferably 2 to 4. Specific examples thereof include
ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,
isobutynyl and isopentynyl groups and the like.
The "lower cycloalkyl group" refers to a cycloalkyl group having 3
to 10 carbon atoms, preferably 3 to 8, especially preferably 3 to
6. Specific examples thereof include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl and
cyclodecanyl groups.
The "aryl group" refers to a residue formed by removing one
hydrogen atom from a monocyclic aromatic hydrocarbon group, or
bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon
having 6 to 14 carbon atoms. Specific examples thereof include
phenyl, naphthyl, anthryl and phenanthryl groups and the like.
The "heterocyclic ring" refers to a saturated or unsaturated
monocyclic heterocyclic ring having one or a plurality of
heteroatoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom in the ring (preferably, a saturated or unsaturated
monocyclic 5 or 6 membered heterocyclic ring having one or two
heteroatoms and 3 to 5 carbon atoms in the ring), or a bicyclic or
tricyclic condensed polycyclic heterocyclic ring (preferably, a
bicyclic or tricyclic condensed polycyclic heterocyclic ring having
one or two heteroatoms and 7 to 13 carbon atoms in the ring).
Specific examples of the "saturated monocyclic heterocyclic ring"
include pyrrolidine, pyrazolidine, imidazolidine, triazolidine,
piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine,
homopiperidine and homopiperazine rings and the like having at
least a nitrogen atom in the ring, tetrahydrofuran and
tetrahydropyran rings and the like having at least an oxygen atom
in the ring, tetrahydrothiophene and tetrahydrothiopyran rings and
the like having a sulfur atom in the ring, oxazolidine,
isoxazolidine and morpholine rings and the like having a nitrogen
atom and an oxygen atom in the ring, and thiazolidine,
isothiazolidine and thiomorpholine rings and the like having a
nitrogen atom and a sulfur atom in the ring.
Further, such a saturated monocyclic heterocyclic ring can be
condensed with a benzene ring or the like to form a bicyclic or
tricyclic condensed polycyclic heterocyclic ring such as a
dihydroindole, dihydroindazole, dihydrobenzimidazole,
tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrocinnoline,
tetrahydrophthalazine, tetrahydroquinazoline,
tetrahydroquinoxaline, dihydrobenzofuran, dihydroisobenzofuran,
chromane, isochromane, dihydrobenzothiophene,
dihydroisobenzothiophene, thiochromane, isothiochromane,
dihydrobenzoxazole, dihydrobenzisoxazole, dihydrobenzoxazine,
dihydrobenzothiazole, dihydrobenzisothiazole, dihydrobenzothiazine,
xanthene, 4a-carbazole, or perimidine ring and the like.
Specific examples of the "unsaturated monocyclic heterocyclic ring"
include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole,
dihydroimidazole, imidazole, dihydrotriazole, triazole,
tetrahydropyridine, dihydropyridine, pyridine,
tetrahydropyridazine, dihydropyridazine, pyridazine,
tetrahydropyrimidine, dihydropyrimidine, pyrimidine,
tetrahydropyrazine, dihydropyrazine and pyrazine rings and the like
having at least a nitrogen atom in the ring, dihydrofuran, furan,
dihydropyran and pyran rings and the like having at least an oxygen
atom in the ring, dihydrothiophene, thiophene, dihydrothiopyran and
thiopyran rings and the like having a sulfur atom in the ring,
dihydrooxazole, oxazole, dihydroisoxazole, isoxazole,
dihydrooxazine and oxazine rings and the like having a nitrogen
atom and an oxygen atom in the ring, dihydrothiazole, thiazole,
dihydroisothiazole, isothiazole, dihydrothiazine and thiazine rings
and the like having a nitrogen atom and a sulfur atom in the
ring.
Further, such an unsaturated monocyclic heterocyclic ring can be
condensed with a benzene ring or the like to form a bicyclic or
tricyclic condensed polycyclic heterocyclic ring such as an indole,
indazole, benzimidazole, benzotriazole, dihydroquinoline,
quinoline, dihydroisoquinoline, isoquinoline, phenanthridine,
dihydrocinnoline, cinnoline, dihydrophthalazine, phthalazine,
dihydroquinazoline, quinazoline, dihydroquinoxaline, quinoxaline,
benzofuran, isobenzofuran, chromene, isochromene, benzothiophene,
isobenzothiophene, thiochromene, isothiochromene, benzoxazole,
benzisoxazole, benzoxazine, benzothiazole, benzisothiazole,
benzothiazine, phenoxanthin, carbazole, .beta.-carboline,
phenanthridine, acridine, phenanthroline, phenazine, phenothiazine
or phenoxazine ring and the like.
Incidentally, among the above "heterocyclic ring", "monocyclic
heterocyclic ring" is defined as the thing which put saturated
monocyclic heterocyclic ring and unsaturated monocyclic
heterocyclic ring together.
The "heterocyclic group" refers to a residue formed by removing a
hydrogen atom from heterocyclic ring mentioned above.
The "lower alkoxy group" refers to a group formed by replacing the
hydrogen atom of a hydroxy group with a lower alkyl group. Specific
examples thereof include methoxy, ethoxy, n-propoxy, n-butoxy,
n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy,
isobutoxy, sec-butoxy, tert-butoxy and isopentoxy groups and the
like.
The "lower alkenyloxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a lower alkenyl group.
Specific examples thereof include vinyloxy, propenyloxy,
butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy,
isopropenyloxy, 2-methyl-1-propenyloxy and 2-methyl-2-butenyloxy
groups and the like.
The "lower alkynyloxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a lower alkynyl group.
Specific examples thereof include ethynyloxy, propynyloxy,
butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy,
isobutynyloxy and isopentynyloxy groups and the like.
The "lower cycloalkyloxy group" refers to a group formed by
replacing the hydrogen atom of a hydroxy group with a lower
cycloalkyl group. Specific examples thereof include cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,
cyclooctyloxy, cyclononanyloxy and cyclodecanyloxy groups.
The "aryloxy group" refers to a group formed by replacing the
hydrogen atom of a hydroxy group with an aryl group. Specific
examples thereof include phenoxy, naphthoxy, anthryloxy and
phenanthryloxy groups and the like.
The "heterocyclic oxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a heterocyclic group.
The "lower alkylthio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a lower alkyl group.
Specific examples thereof include methylthio, ethylthio,
n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio,
n-octylthio, isopropylthio, isobutylthio, sec-butylthio,
tert-butylthio and isopentylthio groups and the like.
The "lower alkenylthio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a lower alkenyl group.
Specific examples thereof include vinylthio, propenylthio,
butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio,
isopropenylthio, 2-methyl-1-propenylthio and 2-methyl-2-butenylthio
groups and the like.
The "lower alkynylthio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a lower alkynyl group.
Specific examples thereof include ethynylthio, propynylthio,
butynylthio, pentynylthio, hexynylthio, heptynylthio, octynylthio,
isobutynylthio and isopentynylthio groups and the like.
The "lower cycloalkylthio group" refers to a group formed by
replacing the hydrogen atom of a mercapto group with a lower
cycloalkyl group. Specific examples thereof include
cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio,
cycloheptylthio and cyclooctylthio groups.
The "arylthio group" refers to a group formed by replacing the
hydrogen atom of a mercapto group with an aryl group. Specific
examples thereof include phenylthio, naphthylthio, anthrylthio and
phenanthrylthio groups and the like.
The "heterocyclic thio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a heterocyclic
group.
The "lower alkylcarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkyl
group. Specific examples thereof include methylcarbonyl,
ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl,
n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl,
isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,
tert-butylcarbonyl and isopentylcarbonyl groups and the like.
The "arylcarbonyl group" refers to a group formed by replacing the
hydrogen atom of a formyl group with an aryl group. Specific
examples thereof include phenylcarbonyl, naphthylcarbonyl,
anthrylcarbonyl and phenanthrylcarbonyl groups and the like.
The "lower alkoxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkoxy
group. Specific examples thereof include methoxycarbonyl,
ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl,
n-pentoxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl,
n-octyloxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl and isopentoxycarbonyl
groups and the like.
The "aryloxycarbonyl group" refers to a group formed by replacing
the hydrogen atom of a formyl group with an aryloxy group. Specific
examples thereof include phenoxycarbonyl, naphthoxycarbonyl,
anthryloxycarbonyl and phenanthryloxycarbonyl groups and the
like.
The "lower alkylcarbonyloxy group" refers to a group formed by
replacing the hydrogen atom of a hydroxy group with a lower
alkylcarbonyl group. Specific examples thereof include
methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,
n-butylcarbonyloxy, n-pentylcarbonyloxy, n-hexylcarbonyloxy,
n-heptylcarbonyloxy, n-octylcarbonyloxy, isopropylcarbonyloxy,
isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy
and isopentylcarbonyloxy groups and the like.
The "arylcarbonyloxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with an arylcarbonyl group.
Specific examples thereof include phenylcarbonyloxy,
naphthylcarbonyloxy, anthrylcarbonyloxy and phenanthrylcarbonyloxy
groups and the like.
The "lower alkylene group" refers to a straight chain or branched
alkylene group having 1 to 8 carbon atoms, preferably 1 to 6,
especially preferably 1 to 4. Specific examples thereof include
methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene, methylmethylene and
ethylmethylene groups and the like.
The "halogenated lower alkyl group" refers to a group formed by
replacing the hydrogen atom of a lower alkyl group with one or a
plurality of halogen atoms. Specific examples thereof include
difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl,
dichloromethyl, trichloromethyl, trichloroethyl, trichloropropyl
and the like.
The "halogenated lower alkoxy group" refers to a group formed by
replacing the hydrogen atom of a lower alkoxy group with one or a
plurality of halogen atoms. Specific examples thereof include
difluoromethoxy, trifluoromethoxy, trifluoroethoxy,
trifluoropropoxy, dichloromethoxy, trichloromethoxy,
trichloroethoxy, trichloropropoxy and the like.
The "lower alkyl group which may have a substituent", "lower
alkenyl group which may have a substituent", "lower alkynyl group
which may have a substituent", "lower alkoxy group which may have a
substituent", "lower alkenyloxy group which may have a substituent"
and/or "lower alkynyloxy group which may have a substituent" refer
to a "lower alkyl group", a "lower alkenyl group", a "lower alkynyl
group", a "lower alkoxy group", a "lower alkenyloxy group" and/or a
"lower alkynyloxy group" which may have one or a plurality of
substituents selected from the following .alpha..sup.1 group,
preferred one or a plurality of substituents selected from the
following .alpha..sup.2 group, respectively.
[.alpha..sup.1 Group]
A halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, a lower alkoxy group, a
halogenated lower alkoxy group, a lower alkenyloxy group, a lower
alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group, a mercapto group, a lower alkylthio group,
a lower alkenylthio group, a lower alkynylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group,
a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group,
a carboxy group, a lower alkoxycarbonyl group, an aryloxycarbonyl
group, a lower alkylcarbonyloxy group, an arylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group.
[.alpha..sup.2 Group]
A halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, a lower alkoxy group, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy
group, an aryloxy group, a heterocyclic oxy group and
--NR.sup.aR.sup.b.
The "lower cycloalkyl group which may have a substituent", "aryl
group which may have a substituent", "heterocyclic group which may
have a substituent", "lower cycloalkyloxy group which may have a
substituent", "aryloxy group which may have a substituent" and/or
"heterocyclic oxy group which may have a substituent" refer to a
"lower cycloalkyl group", an "aryl group", a "heterocyclic group",
a "lower cycloalkyloxy group", an "aryloxy group" and/or a
"heterocyclic oxy group" which may have one or a plurality of
substituents selected from the following .beta. group,
respectively.
[.beta. Group]
A halogen atom, a lower alkyl group, a halogenated lower alkyl
group, a lower alkenyl group, a lower alkynyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy
group, a lower alkoxy group, a halogenated lower alkoxy group, a
lower alkenyloxy group, a lower alkynyloxy group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
mercapto group, a lower alkylthio group, a lower alkenylthio group,
a lower alkynylthio group, a lower cycloalkylthio group, an
arylthio group, a heterocyclic thio group, a formyl group, a lower
alkylcarbonyl group, an arylcarbonyl group, a carboxy group, a
lower alkoxycarbonyl group, an aryloxycarbonyl group, a lower
alkylcarbonyloxy group, an arylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group.
R.sup.a and R.sup.b in the above "--NR.sup.aR.sup.b" may be the
same or different and represent a substituent selected from the
following .gamma..sup.1 group, preferably the following
.gamma..sup.2 group.
[.gamma..sup.1 Group]
A hydrogen atom, a lower alkyl group, a lower alkenyl group, a
lower alkynyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxycarbonyl group and an
aryloxycarbonyl group.
[.gamma..sup.2 Group]
A hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic
group, a lower alkoxycarbonyl group and an aryloxycarbonyl
group.
The term "a plurality of groups" as used in this invention means
that each group may be the same or different and stands for 2 or
more but not more than the number of groups which can be introduced
into substitutable position(s), and the number is preferably 2 or
3, and 2 is particularly preferable.
Further, in this invention, a hydrogen atom and a halogen atom are
also included in the concept of the "group".
The "substituted phenylchalcogeno lower alkyl group" as used herein
refers to a group that a substituted phenyl group binds to a lower
alkyl group through a chalcogen atom.
The "glucocorticoid receptor modulator" as used herein refers to a
modulator that exhibits a pharmaceutical action by binding to
glucocorticoid receptor. Examples thereof include glucocorticoid
receptor agonists, glucocorticoid receptor antagonists and the
like.
The "salt" of the present compound is not particularly limited as
long as it is a pharmaceutically acceptable salt. Examples thereof
include salts with an inorganic acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid,
phosphoric acid or the like; salts with an organic acid such as
acetic acid, fumaric acid, maleic acid, succinic acid, citric acid,
tartaric acid, adipic acid, gluconic acid, glucoheptonic acid,
glucuronic acid, terephthalic acid, methanesulfonic acid, lactic
acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid,
lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid,
stearic acid, tannic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate ester,
methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid or
the like; quaternary ammonium salts with methyl bromide, methyl
iodide or the like; salts with a halogen ion such as a bromine ion,
a chlorine ion, an iodine ion or the like; salts with an alkali
metal such as lithium, sodium, potassium or the like; salts with an
alkaline earth metal such as calcium, magnesium or the like; salts
with a metal such as iron, zinc or the like; salts with ammonia;
salts with an organic amine such as triethylenediamine,
2-aminoethanol, 2,2-iminobis(ethanol),
1-deoxy-1-(methylamino)-2-D-sorbitol,
2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine,
N,N-bis(phenylmethyl)-1,2-ethanediamine or the like.
In the case where there are geometrical isomers and/or optical
isomers in the present compound, these isomers are also included in
the scope of the present invention.
In the case where there are proton tautomers in the present
compound, these tautomers (keto-form, enol-form) are also included
in the scope of the present invention.
In the case where there are hydrate and/or solvate in the present
compound, these hydrate and/or solvate are also included in the
scope of the present invention.
In the case where there are polymorphism and polymorphism group
(polymorphism system) in the present compound, these polymorphism
and polymorphism group (polymorphism system) are also included in
the scope of the present invention. "Polymorphism group
(polymorphism system)" herein means each crystal form in each step
where the crystal form changes depending on conditions and states
(the states also include a state of drug formulation) of
manufacture, crystallization and preservation and the like, and the
entire process.
(a) Preferred examples of the present compound include compounds in
which the respective groups are groups as defined below and salts
thereof in the compounds represented by the general formula (1) and
salts thereof.
(a1) R.sup.1 represents a hydrogen atom or a lower alkyl group;
and/or
(a2) R.sup.2 represents a hydrogen atom or a lower alkyl group;
and/or
(a3) R.sup.3 and R.sup.4 may be the same or different and represent
a hydrogen atom or a lower alkyl group; and/or
(a4) R.sup.5 represents a hydrogen atom or a lower alkyl group;
and/or
(a5) R.sup.6 represents a halogen atom, a lower alkyl group, a
hydroxy group, a lower alkoxy group, a nitro group or a cyano
group; and/or
(a6) X represents --CO--, --C(O)NR.sup.8--, --S(O)-- or
--S(O).sub.2--; and/or
(a7) R.sup.7 and/or R.sup.8 may be the same or different and
represent a hydrogen atom, a lower alkyl group, a lower alkenyl
group, a lower alkynyl group, a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower alkoxy group, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy
group, an aryloxy group or a heterocyclic oxy group;
in the case where R.sup.7 and/or R.sup.8 is a lower alkyl group, a
lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a
lower alkenyloxy group or a lower alkynyloxy group, the lower alkyl
group, lower alkenyl group, lower alkynyl group, lower alkoxy
group, lower alkenyloxy group or lower alkynyloxy group may have
one or a plurality of groups selected from a halogen atom, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy
group, a lower alkoxy group, a lower alkenyloxy group, a lower
alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group and --NR.sup.aR.sup.b as substituent(s);
in the case where R.sup.7 and/or R.sup.8 is a lower cycloalkyl
group, an aryl group, a heterocyclic group, a lower cycloalkyloxy
group, an aryloxy group or a heterocyclic oxy group, the lower
cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkyloxy group, aryloxy group or heterocyclic oxy group may
have one or a plurality of groups selected from a halogen atom, a
lower alkyl group, a halogenated lower alkyl group, an aryl group,
a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl
group, an aryl group, a heterocyclic group, a hydroxy group, a
lower alkoxy group, a halogenated lower alkoxy group, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy
group, an aryloxy group, a heterocyclic oxy group, a mercapto
group, a lower alkylthio group, a lower alkenylthio group, a lower
alkynylthio group, a lower cycloalkylthio group, an arylthio group,
a heterocyclic thio group, a lower alkylcarbonyl group, an
arylcarbonyl group, a lower alkoxycarbonyl group, an
aryloxycarbonyl group, a lower alkylcarbonyloxy group, an
arylcarbonyloxy group, --NR.sup.aR.sup.b, a nitro group and a cyano
group as substituent(s);
R.sup.a and R.sup.b may be the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxycarbonyl group or an
aryloxycarbonyl group; and/or
(a8) Y represents a lower alkylene group; and/or
(a9) Z represents a chalcogen atom; and/or
(a10) p represents 0, 1, 2 or 3, in the case where p is 2 or 3,
each R.sup.6 may be the same or different.
That is, in the compounds represented by the general formula (1)
and salts thereof, preferred examples include compounds that
comprise one or a combination of two or more selected from the
above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9) and
(a10), and salts thereof.
(b) More preferred examples of the present compound include
compounds in which the respective groups are groups as defined
below and salts thereof in the compounds represented by the general
formula (1) and salts thereof.
(b1) R.sup.1 represents a hydrogen atom or a lower alkyl group;
and/or
(b2) R.sup.2 represents a hydrogen atom or a lower alkyl group;
and/or
(b3) R.sup.3 and R.sup.4 may be the same or different and represent
a hydrogen atom or a lower alkyl group; and/or
(b4) R.sup.5 represents a hydrogen atom or a lower alkyl group;
and/or
(b5) R.sup.6 represents a halogen atom, a lower alkyl group, a
hydroxy group, a lower alkoxy group or a nitro group; and/or
(b6) X represents --CO--, --C(O)NR.sup.8--, --S(O)-- or
--S(O).sub.2--; and/or
(b7) R.sup.7 and/or R.sup.8 may be the same or different and
represent a hydrogen atom, a lower alkyl group, a lower alkenyl
group, a lower alkynyl group, a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower alkoxy group, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy
group, an aryloxy group or a heterocyclic oxy group;
in the case where R.sup.7 and/or R.sup.8 is a lower alkyl group, a
lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a
lower alkenyloxy group or a lower alkynyloxy group, the lower alkyl
group, lower alkenyl group, lower alkynyl group, lower alkoxy
group, lower alkenyloxy group or lower alkynyloxy group may have
one or a plurality of groups selected from a halogen atom, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy
group, a lower alkoxy group, a lower cycloalkyloxy group, an
aryloxy group, a heterocyclic oxy group and --NR.sup.aR.sup.b as
substituent(s);
in the case where R.sup.7 and/or R.sup.8 is a lower cycloalkyl
group, an aryl group, a heterocyclic group, a lower cycloalkyloxy
group, an aryloxy group or a heterocyclic oxy group, the lower
cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkyloxy group, aryloxy group or heterocyclic oxy group may
have one or a plurality of groups selected from a halogen atom, a
lower alkyl group, a halogenated lower alkyl group, a lower
cycloalkyl group, an aryl group, a hydroxy group, a lower alkoxy
group, a halogenated lower alkoxy group, a cycloalkyloxy group, an
aryloxy group, a mercapto group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group,
a lower alkylcarbonyl group, an arylcarbonyl group, a lower
alkoxycarbonyl group, an aryloxycarbonyl group, a lower
alkylcarbonyloxy group, an arylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group as
substituent(s);
R.sup.a and R.sup.b may be the same or different and represent a
hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group;
and/or
(b8) Y represents a lower alkylene group; and/or
(b9) Z represents an oxygen atom or a sulfur atom; and/or
(b10) p represents 0, 1, 2 or 3, in the case where p is 2 or 3,
each R.sup.6 may be the same or different.
That is, in the compounds represented by the general formula (1)
and salts thereof, more preferred examples include compounds that
comprise one or a combination of two or more selected from the
above (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9) and
(b10), and salts thereof.
(c) Further more preferred examples of the present compound include
compounds in which the respective groups are groups as defined
below and salts thereof in the compounds represented by the general
formula (1) and salts thereof.
(c1) R.sup.1 represents a lower alkyl group; and/or
(c2) R.sup.2 represents a hydrogen atom; and/or
(c3) R.sup.3 and R.sup.4 represent a lower alkyl group; and/or
(c4) R.sup.5 represents a lower alkyl group; and/or
(c5) R.sup.6 represents a halogen atom, a lower alkyl group, a
hydroxy group, a lower alkoxy group or a nitro group; and/or
(c6) X represents --CO--, --C(O)NR.sup.8-- or --S(O).sub.2--;
and/or
(c7) R.sup.7 represents a lower alkyl group, a lower alkenyl group,
a lower cycloalkyl group, an aryl group, a heterocyclic group, a
lower alkoxy group or an aryloxy group;
in the case where R.sup.7 is a lower alkyl group or a lower alkoxy
group, the lower alkyl group or lower alkoxy group may have one or
a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a lower alkoxy group and --NR.sup.aR.sup.b as
substituent(s);
in the case where R.sup.7 is an aryl group, a heterocyclic group or
an aryloxy group, the aryl group, heterocyclic group or aryloxy
group may have one or a plurality of groups selected from a halogen
atom, a lower alkyl group, a halogenated lower alkyl group, an aryl
group, a hydroxy group, a lower alkoxy group, a halogenated lower
alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group,
a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group,
--NR.sup.aR.sup.b, a nitro group and a cyano group as
substituent(s);
R.sup.a and R.sup.b may be the same or different and represent a
hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group;
and/or
(c8) R.sup.8 represents a hydrogen atom or a lower alkyl group;
in the case where R.sup.8 is a lower alkyl group, the lower alkyl
group may have one or a plurality of groups selected from an aryl
group or a heterocyclic group as substituent(s); and/or
(c9) Y represents a lower alkylene group; and/or
(c10) Z represents an oxygen atom; and/or
(c11) p represents 0, 1 or 2, in the case where p is 2, each
R.sup.6 may be the same or different.
That is, in the compounds represented by the general formula (1)
and salts thereof, further more preferred examples include
compounds that comprise one or a combination of two or more
selected from the above (c1), (c2), (c3), (c4), (c5), (c6), (c7),
(c8), (c9), (c10) and (c11), and salts thereof.
(d) Further more preferred examples of the present compound include
compounds in which the respective groups are groups as defined
below and salts thereof in the compounds represented by the general
formula (1) and salts thereof.
(d1) R.sup.1 represents a lower alkyl group; and/or
(d2) R.sup.2 represents a hydrogen atom; and/or
(d3) R.sup.3 and R.sup.4 represent a lower alkyl group; and/or
(d4) R.sup.5 represents a lower alkyl group; and/or
(d5) R.sup.6 represents a halogen atom, a lower alkyl group, a
hydroxy group, a lower alkoxy group or a nitro group; and/or
(d6) X represents --CO--, --C(O)NR.sup.8-- or --S(O).sub.2--;
and/or
(d7) R.sup.7 represents a lower alkyl group, a lower alkenyl group,
a lower cycloalkyl group, an aryl group, a heterocyclic group, a
lower alkoxy group or an aryloxy group;
in the case where R.sup.7 is a lower alkyl group, the lower alkyl
group may have one or a plurality of groups selected from a halogen
atom, an aryl group, a heterocyclic group, a lower alkoxy group and
--NR.sup.aR.sup.b as substituent(s);
in the case where R.sup.7 is an aryl group, the aryl group may have
one or a plurality of groups selected from a halogen atom, a lower
alkyl group, a halogenated lower alkyl group, a lower alkoxy group,
a halogenated lower alkoxy group, a lower alkylthio group, a lower
alkylcarbonyl group, a lower alkoxycarbonyl group, a lower
alkylcarbonyloxy group, --NR.sup.aR.sup.b, a nitro group and a
cyano group as substituent(s);
in the case where R.sup.7 is a heterocyclic group, the heterocyclic
group may have one or a plurality of groups selected from a halogen
atom, a lower alkyl group, an aryl group, a hydroxy group, a lower
alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group,
a lower alkoxycarbonyl group or a nitro group as
substituent(s);
in the case where R.sup.7 is a lower alkoxy group, the lower alkoxy
group may have one or a plurality of aryl group as
substituent(s);
in the case where R.sup.7 is an aryloxy group, the aryloxy group
may have one or a plurality of groups selected from a halogen atom
and a lower alkoxy group as substituent(s);
R.sup.a and R.sup.b may be the same or different and represent a
hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group;
and/or
(d8) R.sup.8 represents a hydrogen atom or a lower alkyl group;
in the case where R.sup.8 is a lower alkyl group, the lower alkyl
group may have one or a plurality of groups selected from an aryl
group or a heterocyclic group as substituent(s); and/or
(d9) Y represents a lower alkylene group; and/or
(d10) Z represents an oxygen atom; and/or
(d11) p represents 0, 1 or 2, in the case where p is 2, each
R.sup.6 may be the same or different.
That is, in the compounds represented by the general formula (1)
and salts thereof, further more preferred examples include
compounds that comprise one or a combination of two or more
selected from the above (d1), (d2), (d3), (d4), (d5), (d6), (d7),
(d8), (d9), (d10) and (d11), and salts thereof.
(e) Specific examples of the present compound represented by the
preferred substituent(s) include compounds in which Z represents an
oxygen atom in the general formula (1) and satisfy the above
conditions (a) and/or (b), and salts thereof.
(f) Other specific examples of the present compound represented by
the preferred substituent(s) include compounds in which R.sup.1,
R.sup.3, R.sup.4 and R.sup.5 represent a methyl group, R.sup.2
represents a hydrogen atom, Y represents a methylene group in the
general formula (1) and satisfy the above conditions (a), (b), (c)
and/or (d), and salts thereof.
(g) Particularly preferred specific examples of the present
compound include the following compounds and salts thereof.
6-(4-Benzoyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-
-trimethyl-1,2-dihydroquinoline,
6-(4-t-Butoxycarbonylaminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylph-
enoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxybenzoyloxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Cyclohexylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-3-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Butyryloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-
-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-propionyloxyphenyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
6-(4-Acryloyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,-
4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiophen-3-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(furan-2-ylcarbonyloxy)-2-methoxy-
phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-isobutyryloxy-2-methoxyphenyl)-2,-
2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-phenylacetoxyphenyl)-2,-
2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-propionyloxyphenyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiophen-2-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-phenylpropionyloxy)p-
henyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(furan-3-ylcarbonyloxy)-2-methoxy-
phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-2-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-nitrobenzoyloxy)phen-
yl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-(pyridin-2-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-(pyridin-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Acetoxybenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(1-t-Butoxycarbonylpiperidin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5--
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methylthiobenzoyloxy-
)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(1-t-Butoxycarbonylimidazol-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-f-
luoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-4-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-5-ylcarbonylox-
y)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(oxazol-4-ylcarbonyloxy-
)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(3-Acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(3-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-methylfuran-2-ylcarb-
onyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-3-ylacetoxy)ph-
enyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(4-Acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxycarbonylbenzo-
yloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(6-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methylpyridin-3-ylca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methylfuran-2-ylcarb-
onyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-t-Butylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethy-
l)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyrimidin-5-ylcarbonyl-
oxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-nitrofuran-2-ylcarbo-
nyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Chloropyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-met-
hylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(3-fluoropyridin-4-ylcarbonyloxy)-
-2-methoxyphenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-methyl-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(pyridin-3-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nitrophenox-
ymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(Furan-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-5-(2-methoxy-5-ni-
trophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-methoxy-5-nitrophenoxyme-
thyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(2-Methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-(thiophen-3-ylcarbonylo-
xy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(Furan-3-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nit-
rophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxypyridin-3-ylc-
arbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Aminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2-
,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-propylsulfonyloxyphenyl-
)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Ethylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-isopropylsulfonyl
oxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Butylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(2-Methoxy-5-nitrophenoxymethyl)-6-(2-methoxy-4-propylsulfonyloxyphenyl-
)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Cyclopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methoxy-5-nitrophenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Isopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methoxy-5-nitrophenoxymet-
hyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Ethylsulfonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxymethyl)--
2,2,4-trimethyl-1,2-dihydroquinoline,
6-(2-Methoxy-4-propylsulfonyloxyphenyl)-5-(2-methyl-5-nitrophenoxymethyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Isopropylsulfonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxymeth-
yl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Cyclopropylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-isobutylsulfonyloxy-2-methoxyphen-
yl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Cyclopentylsulfonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxym-
ethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3,3,3-trifluoropropyls-
ulfonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-methoxyphenoxycarbon-
yloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(2-Chlorophenylaminocarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-meth-
ylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methoxyphenylaminoca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxyphenylaminoca-
rbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-methoxycarbonylpheny-
laminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenox-
ymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-(4-Cyanophenylaminocarbonyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-methy-
lphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(morpholin-4-ylcarbonyl-
oxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Isopropylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylpheno-
xymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-methoxy-5-nitrophe-
noxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[2-Methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-methyl-5-nitrophen-
oxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-(4-Dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(2-methyl-5-nitrophenoxy-
methyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-[N-Benzyl-N-(2-dimethylaminoethyl)aminocarbonyloxy]-2-methoxyphenyl]-
-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline,
6-[4-[N-(2-Dimethylaminoethyl)-N-(pyridin-3-ylmethyl)aminocarbonyloxy]-2--
methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihy-
droquinoline,
6-[4-[N-(2-Dimethylaminoethyl)-N-ethylaminocarbonyloxy]-2-methoxyphenyl]--
5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline.
The present compound can be synthesized according to the following
procedures. The individual concrete preparation procedures are
explained in details in the section of "Production Examples" in
Examples. These examples are intended to make the present invention
more clearly understandable, and do not limit the scope of the
present invention. The hal shown in the following synthetic routes
represents a halogen atom.
The present compound (I)-(a) (the compound in which Y is a
methylene group, R.sup.2 is H, R.sup.3, R.sup.4 and R.sup.5 are
methyl groups, X is C(O) in the general formula (1)) can be
synthesized according to the synthetic route 1. Namely, the
compound (I)-(a) can be given by the reaction of the compound (II)
with a corresponding halide (III) in an organic solvent such as
methylene dichloride, N,N-dimethylformamide (hereinafter referred
to as DMF) in the presence of a base such as triethylamine,
diisopropylethylamine (hereinafter referred to as DIEA) at
0.degree. C. to room temperature for 1 hour to 2 days.
And the compound (I)-(a) can be given by the reaction of the
compound (II) with a corresponding carboxylic acid (IV) in an
organic solvent such as methylene dichloride, DMF in the presence
of a base such as triethylamine, DIEA and a condensation agent such
as N,N'-dicyclohexylcarbodiimide,
O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium
hexafluorophosphate at 0.degree. C. to room temperature for 30
minutes to 3 days.
##STR00003##
The present compound (I)-(b) (the compound in which Y is a
methylene group, R.sup.2 is H, R.sup.3, R.sup.4 and R.sup.5 are
methyl groups, X is S(O).sub.2 in the general formula (1)) can be
synthesized according to the synthetic route 2. Namely, the
compound (I)-(b) can be given by the reaction of the compound (II)
with a corresponding halide (V) in an organic solvent such as
methylene dichloride, DMF in the presence of a base such as
triethylamine, DIEA at 0.degree. C. to room temperature for 1 hour
to 2 days.
##STR00004##
The present compound (I)-(c) (the compound in which Y is a
methylene group, R.sup.2 is H, R.sup.3, R.sup.4 and R.sup.5 are
methyl groups, X is C(O)NR.sup.8 and R.sup.8 is a hydrogen atom in
the general formula (1)) can be synthesized according to the
synthetic route 3. Namely, the compound (I)-(c) can be given by the
reaction of the compound (II) with a corresponding isocyanate (VI)
in an organic solvent such as methylene dichloride, DMF in the
presence of a base such as triethylamine, DIEA at 0.degree. C. to
room temperature for 30 minutes to 1 day.
##STR00005##
The present compound (I)-(d) (the compound in which Y is a
methylene group, R.sup.2 is H, R.sup.3, R.sup.4 and R.sup.5 are
methyl groups, X is C(O)NR.sup.8 in the general formula (1)) can be
synthesized according to the synthetic route 4. Namely, the
compound (I)-(d) can be given by the reaction of the compound (II)
with 1,1'-carbonyldiimidazole in an organic solvent such as
methylene dichloride, tetrahydrofuran (hereinafter referred to as
THF) at room temperature to 50.degree. C. for 30 minutes to 12
hours followed by the reaction with a corresponding amine (VII) at
room temperature to 50.degree. C. for 30 minutes to 5 hours.
##STR00006##
The compound (II) can be synthesized according to the synthetic
route 5. Namely, the compound (IX) can be given by the reaction of
the compound (VIII) with methanesulfonyl chloride in an organic
solvent such as methylene dichloride, DMF in the presence of a base
such as triethylamine, DIEA at 0.degree. C. to room temperature for
30 minutes to 3 days. The compound (XI) can be given by the
reaction of the obtained compound (IX) with a corresponding phenol
or thiol (X) in an organic solvent such as DMF, methylene
dichloride in the presence of a base such as potassium carbonate,
DIEA, sodium hydride at 50.degree. C. to 100.degree. C. for 1 hour
to 2 days. The compound (II) can be given by the treatment of the
obtained compound (XI) in an organic solvent such as methylene
dichloride, 1,4-dioxane in the presence of an acid such as hydrogen
chloride, trifluoroacetic acid.
##STR00007##
The compound (XI)-(a) (the compound in which Z is an oxygen atom in
the compound (XI)) can be synthesized according to the synthetic
route 6. Namely, the compound (XI)-(a) can be given by the reaction
of the compound (VIII) with a corresponding phenol (XII) in an
organic solvent such as benzene, THF in the presence of a phosphine
such as triphenylphosphine, tributylphosphine and a reagent such as
diethylazodicarboxylate, diisopropylazodicarboxylate,
1,1'-(azodicarbonyl)dipiperidine at room temperature for 1 hour to
2 days.
##STR00008##
The compound (VIII) can be synthesized according to the synthetic
route 7. Namely, the compound (XV) can be given by the reaction of
a boronic acid (XIII) with a halide or triflate (XIV) in a solvent
such as DMF, ethanol, toluene, water in the presence of a base such
as cesium carbonate, sodium carbonate, potassium phosphate and a
catalyst such as bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50.degree. C. to
120.degree. C. for 12 hours to 2 days. The compound (XVI) can be
given by the treatment of the obtained compound (XV) in a solvent
such as methylene dichloride, THF in the presence of an acid such
as boron tribromide, hydrogen chloride at -78.degree. C. to room
temperature for 1 hour to 1 day. The compound (XVII) can be given
by the treatment of the obtained compound (XVI) under hydrogen
atmosphere in an organic solvent such as methanol, ethanol,
1,4-dioxane, THF in the presence of a catalyst such as palladium
carbon, platinum dioxide at room temperature for 2 hours to 2 days.
The compound (XVIII) can be given by the treatment of the obtained
compound (XVII) in acetone in the presence of iodine at 80.degree.
C. to 130.degree. C. for 24 hours to 5 days. The compound (XIX) can
be given by the reaction of the obtained compound (XVIII) with
chlorodimethylether in an organic solvent such as methylene
dichloride, DMF in the presence of a base such as potassium
carbonate, triethylamine, DIEA. The compound (XX) can be given by
the treatment of the obtained compound (XIX) in an organic solvent
such as diethyl ether, THF and in the presence of a reducing agent
such as lithium aluminium hydride at 0.degree. C. to 50.degree. C.
for 1 hour to 1 day. The compound (VIII) can be given by the
reaction of the obtained compound (XX) with a corresponding halide
(XXI) in an organic solvent such as DMF, ethanol in the presence of
a base such as potassium carbonate, DIEA at room temperature to
100.degree. C. for 1 hour to 24 hours.
##STR00009## ##STR00010##
A detailed explanation of this matter will be described in the
section of "Pharmacological Test" in Examples described below. In
order to find the usefulness of the present compound as a
pharmaceutical, a glucocorticoid receptor competitor assay was
carried out by a fluorescence polarization method by using a
glucocorticoid receptor competitor assay kit (manufactured by
Invitrogen, cat No P2816) to study the glucocorticoid receptor
binding activity of the present compound. As a result, the present
compound showed an excellent glucocorticoid receptor binding
activity to the glucocorticoid receptor.
Incidentally, the glucocorticoid receptor is associated with the
occurrence of various diseases as described above, therefore, the
present compound having an excellent binding activity to the
glucocorticoid receptor is useful as a glucocorticoid receptor
modulator.
The present compound can be administered either orally or
parenterally. Examples of the dosage form include a tablet, a
capsule, a granule, a powder, an injection, an eye drop, a
suppository, percutaneous absorption preparation, an ointment, an
aerosol (including an inhalant) and the like and such a preparation
can be prepared using a commonly used technique.
For example, an oral preparation such as a tablet, a capsule, a
granule or a powder can be prepared by optionally adding a
necessary amount of an excipient such as lactose, mannitol, starch,
crystalline cellulose, light silicic anhydride, calcium carbonate
or calcium hydrogen phosphate; a lubricant such as stearic acid,
magnesium stearate or talc; a binder such as starch, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone; a
disintegrant such as carboxymethyl cellulose, low-substituted
hydroxypropylmethyl cellulose or calcium citrate; a coating agent
such as hydroxypropylmethyl cellulose, macrogol or a silicone
resin; a stabilizer such as ethyl p-hydroxybenzoate or benzyl
alcohol; a corrigent such as a sweetener, a sour agent or a flavor,
or the like.
A parenteral preparation such as an injection or an eye drop can be
prepared by optionally adding a necessary amount of a tonicity
agent such as sodium chloride, concentrated glycerin, propylene
glycol, polyethylene glycol, potassium chloride, sorbitol or
mannitol; a buffer such as sodium phosphate, sodium hydrogen
phosphate, sodium acetate, citric acid, glacial acetic acid or
trometamol; a surfactant such as polysorbate 80, polyoxy 40
stearate or polyoxyethylene hydrogenated castor oil 60; a
stabilizer such as sodium citrate or sodium edetate; a preservative
such as benzalkonium chloride, paraben, benzothonium chloride,
p-hydroxybenzoate ester, sodium benzoate or chlorobutanol; a pH
adjusting agent such as hydrochloric acid, citric acid, phosphoric
acid, glacial acetic acid, sodium hydroxide, sodium carbonate or
sodium hydrogen carbonate; a soothing agent such as benzyl alcohol,
or the like.
This invention also provides a preventive or therapeutic method for
glucocorticoid receptor related diseases, for examples, metabolic
disorders such as diabetes and obesity, inflammatory diseases such
as enteritis and chronic obstructive pulmonary diseases, autoimmune
diseases such as connective tissue diseases, allergic diseases such
as asthma, atopic dermatitis and allergic rhinitis, central nervous
system diseases such as psychiatric disorders, Alzheimer's disease
and drug use disorders, cardiovascular diseases such as
hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma and the like.
The dose of the present compound can be appropriately selected
depending on the kinds of the diseases, symptoms, age, dosage form
or the like. For example, in the case of an oral preparation, it
can be administered in an amount of generally 0.01 to 1000 mg,
preferably 1 to 100 mg per day in a single dose or several divided
doses. Further, in the case of an eye drop, a preparation
containing the present compound at a concentration of generally
0.0001% to 10% (w/v), preferably 0.01% to 5% (w/v) can be
administered in a single dose or several divided doses.
Hereinafter, Production Examples of the present compound,
Preparation Examples and results of Pharmacological Test will be
described. However, these examples are described for the purpose of
understanding the present invention better and are not meant to
limit the scope of the present invention.
PRODUCTION EXAMPLES
Reference Example 1
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-d-
ihydroquinoline (Reference Compound No. 1-1)
Methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (Reference Compound
No. 1-1-(1))
A mixture of 2,4-dimethoxyphenylboronic acid (25.0 g, 137 mmol),
methyl 2-bromo-5-nitrobenzoate (35.7 g, 137 mmol), cesium carbonate
(89.4 g, 274 mmol) and bis(triphenylphosphine)palladium (II)
dichloride (4.81 g, 6.85 mmol) was suspended in
N,N-dimethylformamide (450 mL), and then the suspension was stirred
under argon atmosphere at 80.degree. C. overnight. After cooling
down, ethyl acetate (200 mL), diethylether (400 mL) and water (1000
mL) were added thereto and the mixture was separated into a water
phase and an organic layer. The water layer was extracted with a
mixed solvent of ethyl acetate (150 mL)-diethylether (150 mL)
(twice). The combined organic layer was washed with water (500 mL,
3 times) and saturated brine (500 mL) successively, dried over
anhydrous magnesium sulfate, and then the solvent was removed under
reduced pressure to give the titled reference compound as a brown
oil. (Quantitative)
TABLE-US-00001 ##STR00011## .sup.1H-NMR (400 MHz, CDCl3) .delta.
3.71 (s, 3H), 3.76 (s, 3H), 3.87 (s, 3H), 6.49 (d, J = 2.3 Hz, 1H),
6.60 (dd, J = 8.3, 2.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.49 (d,
J = 8.5 Hz, 1H), 8.35 (dd, J = 8.5, 2.5 Hz, 1H), 8.67 (d, J = 2.5
Hz, 1H)
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No.
1-1-(2))
A solution of methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate
(Reference Compound No. 1-1-(1), 43.5 g, 137 mmol) in anhydrous
methylene dichloride (250 mL) was cooled to -78.degree. C., boron
tribromide (96.2 g, 384 mmol) was added thereto, and then the
mixture was stirred at room temperature for 1 hour. The mixture was
cooled to -50.degree. C. and methanol (300 mL) was added thereto.
The resulting precipitates were filtered off with methanol to give
the titled reference compound (18.0 g) as a yellow solid. (Yield
51%)
TABLE-US-00002 ##STR00012## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 6.81 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H),
8.28 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 8.9 Hz, 1H), 8.60 (dd, J =
8.9, 2.4 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 10.75 (s, 1H)
8-Amino-3-hydroxybenzo[c]chromen-6-one (Reference Compound No.
1-1-(3))
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No.
1-1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150
mL)-N,N-dimethylformamide (600 mL), 10% palladium on charcoal (5.00
g) was added thereto, and then the reaction mixture was stirred
under hydrogen atmosphere (3 kgf/cm.sup.2) at room temperature
overnight. After the unsoluble materials were filtered out, the
methanol was removed under reduced pressure. Water (2 L) was added
to the residue. The precipitated solid was filtered off and dried
at 90.degree. C. under reduced pressure to give the titled
reference compound (44.02 g) as a pale yellow solid. (Yield
96%)
TABLE-US-00003 ##STR00013## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 6.02 (s, 2H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.37-7.41 (m,
1H), 7.37 (d, J = 2.4 Hz, 1H), 7.96 (ddd, J = 9.3, 5.4, 2.2 Hz,
1H), 8.08 (d, J = 8.5, Hz, 1H)
8-Hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one
(Reference Compound No. 1-1-(4))
In a pressure tube, 8-amino-3-hydroxybenzo[c]chromen-6-one
(Reference Compound No. 1-1-(3), 40.0 g, 176 mmol) was dissolved in
acetone (440 mL)-N-methylpyrrolidone (240 mL), iodine (17.9 g, 70.5
mmol) was added thereto, the pressure tube was sealed, and then the
reaction mixture was stirred at 110.degree. C. for 3 days. After
cooling down, acetone was removed under reduced pressure. To the
obtained residue, ethyl acetate (700 mL), hexane (150 mL) and 1%
aqueous sodium thiosulfate solution (700 mL) were added thereto and
the mixture was separated into a water phase and an organic layer.
The water layer was extracted with a mixed solvent of ethyl acetate
(250 mL)-hexane (50 mL) (3 times). The combined organic layer was
washed with water (500 mL, 3 times) and saturated brine (500 mL)
successively, dried over anhydrous magnesium sulfate, and then the
solvent was removed under reduced pressure. To the obtained
residue, chloroform (150 mL) was added and the unsoluble materials
were filtered out. After the filtrate was concentrated, the residue
was purified by silica gel column chromatography (hexane-ethyl
acetate) to give the titled reference compound (26.0 g) as a yellow
solid. (Yield 48%)
TABLE-US-00004 ##STR00014## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.23 (s, 6H), 1.97 (s, 3H), 5.48 (s, 1H), 7.05 (s, 1H),
7.19 (d, J = 8.9 Hz, 1H), 7.37 (td, J = 9.7, 7.6 Hz, 1H), 7.95
(ddd, J = 9.7, 5.2, 1.8 Hz, 1H), 7.98 (d, J = 8.9, Hz, 1H)
8-Methoxymethoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one
(Reference Compound No. 1-1-(5))
A mixture of
8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one
(Reference Compound No. 1-1-(4), 1.00 g, 3.25 mmol),
chlorodimethylether (420 .mu.L, 5.53 mmol) and potassium carbonate
(1.35 g, 9.77 mmol) was suspended in anhydrous
N,N-dimethylformamide (15 mL) and the suspension was stirred at
50.degree. C. overnight. After cooling down, ethyl acetate (100 mL)
and diethylether (100 mL) were added thereto. The whole was washed
with water (150 mL, 100 mL) and saturated brine (100 mL)
successively, dried over anhydrous magnesium sulfate, and then the
solvent was removed under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane-ethyl
acetate) to give the titled reference compound (747 mg) as a yellow
solid. (Yield 66%)
TABLE-US-00005 ##STR00015## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.22 (s, 6H), 1.95 (s, 3H), 3.40 (s, 3H), 5.27 (s, 2H),
5.43 (s, 1H), 6.85 (s, 1H), 6.98 (d, J = 9.3 Hz, 1H), 6.99 (s, 1H),
7.16 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.04 (d, J =
9.3 Hz, 1H)
6-(2-Hydroxy-4-methoxymethoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-d-
ihydroquinoline (Reference Compound No. 1-1-(6))
Lithium aluminum hydride (167 mg, 4.40 mmol) was suspended in
anhydrous tetrahydrofuran (3 mL). A solution of
8-methoxymethoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one
(Reference Compound No. 1-1-(5), 744.1 mg, 2.12 mmol) in anhydrous
tetrahydrofuran (10 mL) was added dropwise to the suspension at
0.degree. C., the reaction mixture was stirred at the same
temperature for 30 minutes. Ethyl acetate (2 mL) and water (1 mL)
were added to the reaction mixture successively, and then ethyl
acetate (150 mL) was added thereto. 1N aqueous HCl solution (6 mL)
was added, the mixture was washed with water (100 mL, twice) and
saturated brine (50 mL) successively, and then dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure
to give the titled reference compound (750.6 mg) as a pale yellow
amorphous product. (Quantitative)
TABLE-US-00006 ##STR00016## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.13 (s, 3H), 1.20 (s, 3H), 2.23 (s, 3H), 3.39 (s, 3H),
4.26 (dd, J = 11.0, 6.6 Hz, 1H), 4.33 (t, J = 6.6 Hz, 1H), 4.44
(dd, J = 11.0, 6.6 Hz, 1H), 5.14 (s, 2H), 5.33 (s, 1H), 5.76 (s,
1H), 6.49 (dd, J = 8.4, 2.6 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 6.56
(d, J = 2.6 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.4 Hz,
1H), 9.23 (s, 1H)
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-d-
ihydroquinoline (Reference Compound No. 1-1)
A mixture of
6-(2-hydroxy-4-methoxymethoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2--
dihydroquinoline (Reference Compound No. 1-1-(6), 746.1 mg, 2.10
mmol), methyl iodide (131 .mu.L, 2.10 mmol) and potassium carbonate
(582 mg, 4.21 mmol) was suspended in anhydrous
N,N-dimethylformamide (10 mL) and the suspension was stirred at
50.degree. C. for 1 hour. After cooling down, the mixture was
diluted with ethyl acetate (50 mL) and diethylether (50 mL). The
mixture was washed with water (100 mL, twice) and saturated brine
(50 mL) successively, dried over anhydrous magnesium sulfate, and
then the solvent was removed under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to give the titled reference compound (513.2
mg) as a colorless solid. (Yield 66%)
TABLE-US-00007 ##STR00017## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.13 (s, 3H), 1.20 (s, 3H), 2.23 (s, 3H), 3.41 (s, 3H),
3.65 (s, 3H), 4.14 (d, J = 12.2 Hz, 1H), 4.33 (br s, 1H), 4.45 (d,
J = 12.2 Hz, 1H), 5.22 (s, 2H), 5.32 (s, 1H), 5.78 (s, 1H), 6.51
(d, J = 8.3 Hz, 1H), 6.61-6.64 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H),
7.05 (d, J = 8.3 Hz, 1H)
Using available compounds, the following Reference Compound No. 1-2
was obtained by a method similar to that of Reference Compound No.
1-1.
TABLE-US-00008 5-Hydroxymethyl-6-(2-methoxy-5-
methoxymethoxyphenyl)-2,2,4-trimethyl- 1,2-dihydroquinoline
(Reference Compound No. 1-2) ##STR00018## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.13 (s, 3H), 1.21 (s, 3H), 2.24 (s, 3H),
3.38 (s, 3H), 3.62 (s, 3H), 4.15 (dd, J = 12.2, 4.7 Hz, 1H), 4.38
(t, J = 4.7 Hz, 1H), 4.47 (dd, J = 12.2, 4.7 Hz, 1H), 5.11 (d, J =
6.5 Hz, 1H), 5.13 (d, J = 6.5 Hz, 1H), 5.33 (s, 1H), 5.84 (s, 1H),
6.53 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.85 (d, J =
2.6 Hz,1H), 6.90-6.96 (m, 2H)
Reference Example 2
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methoxymethoxyphenyl)-2,-
2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1)
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2--
dihydroquinoline (Reference Compound No. 1-1, 511.7 mg, 1.39 mmol),
5-fluoro-2-methylphenol (182 .mu.L, 1.67 mmol),
tri-n-butylphosphine (521 .mu.L, 2.09 mmol), and
1,1'-(azodicarbonyl)dipiperidine (526 mg, 2.08 mmol) were dissolved
in anhydrous benzene (8 mL), and then the mixture was stirred under
argon atmosphere at room temperature for 1 hour. Hexane (15 mL) was
added to the reaction mixture, and the unsoluble materials were
filtered out. The filtrate was concentrated under reduced pressure
and the residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to give the titled reference compound (411.4
mg) as a colorless amorphous product. (Yield 62%)
TABLE-US-00009 ##STR00019## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.13 (s, 3H), 1.20 (s, 3H), 2.23 (s, 3H), 3.41 (s, 3H),
3.65 (s, 3H), 4.14 (d, J = 12.2 Hz, 1H), 4.33 (br s, 1H), 4.45 (d,
J = 12.2 Hz, 1H), 5.22 (s, 2H), 5.32 (s, 1H), 5.78 (s, 1H), 6.51
(d, J = 8.3 Hz, 1H), 6.61- 6.64 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H),
7.05 (d, J = 8.3 Hz, 1H)
Using Reference Compound No. 1-1 or 1-2, the following Reference
Compounds (No. 2-2.about.2-4) were obtained by a method similar to
that of Reference Compound No. 2-1.
TABLE-US-00010 5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-
methoxy-5-methoxymethoxyphenyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-2)
##STR00020## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 1.05 (s,
3H), 1.15 (s, 3H), 2.02 (s, 3H), 2.08 (s, 3H), 3.29 (s, 3H), 3.67
(s, 3H), 4.62 (d, J = 12.1 Hz, 1H), 5.02 (d, J = 6.7 Hz, 1H), 5.06
(d, J = 6.7 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.02
(s, 1H), 6.35 (dd, J = 11.6, 2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4
Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.86
(d, J = 2.7 Hz, 1H), 6.95 (dd, J = 8.9, 2.7 Hz, 1H), 6.97 (d, J =
8.9 Hz, 1H), 7.02- 7.05 (m, 1H)
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-
(2-methyl-5-nitrophenoxymethyl)-2,2,4-
trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-3)
##STR00021## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.87 (s,
3H), 1.17 (s, 3H), 2.13 (s, 3H), 2.18 (s, 3H), 3.39 (s, 3H), 3.72
(s, 3H), 4.79 (d, J = 12.7 Hz, 1H), 5.21 (s, 2H), 5.31 (d, J = 12.7
Hz, 1H), 5.38 (s, 1H), 5.97 (s, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.65
(dd, J = 8.2, 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.76 (d, J =
8.2 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H),
7.32 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.7, 2.1 Hz, 1H)
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Reference Compound No. 2-4) ##STR00022## 1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.01 (s, 3H), 1.17 (s, 3H), 2.14 (s, 3H),
3.67 (s, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 4.67 (d, J = 12.1 Hz,
1H), 5.17 (s, 2H), 5.25 (d, J = 12.1 Hz, 1H), 5.38 (s, 1H), 5.96
(s, 1H), 6.54 (dd, J = 8.4, 2.3 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H),
6.64 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 7.04 (d, J =
8.4 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 2.7 Hz, 1H),
7.80 (dd, J = 8.9, 2.7 Hz, 1H)
Reference Example 3
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tri-
methyl-1,2-dihydroquinoline (Reference Compound No. 3-1)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methoxymethoxyphenyl)-2-
,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1,
424 mg, 0.888 mmol) was dissolved in 1,4-dioxane (5 mL), 4N
HCl/1,4-dioxane solution (666 .mu.L) was added thereto, and then
the mixture was stirred at room temperature overnight. The mixture
was diluted with ethyl acetate (150 mL). The mixture was washed
with water (100 mL, twice) and saturated brine (50 mL)
successively, dried over anhydrous magnesium sulfate, and then the
solvent was removed under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane-ethyl
acetate) to give the titled reference compound (241.7 mg) as a
colorless solid. (Yield 63%)
TABLE-US-00011 ##STR00023## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.00 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H), 2.08 (s, 3H),
3.67 (s, 3H), 4.63 (d, J = 12.1 Hz, 1H), 5.08 (d, J = 12.1 Hz, 1H),
5.37 (s, 1H), 5.90 (s, 1H), 6.29 (dd, J = 11.5, 2.4 Hz, 1H), 6.36
(dd, J = 8.1, 2.3 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.50 (td, J =
8.4, 2.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz,
1H), 6.94 (d, J = 8.1 Hz, 1H), 7.00- 7.04 (m, 1H), 9.46 (s, 1H)
Using any compounds among Reference Compounds No. 2-2.about.2-4,
the following Reference Compounds (No. 3-2.about.3-4) were obtained
by a method similar to that of Reference Compound No. 3-1.
TABLE-US-00012 5-(5-Fluoro-2-methylphenoxymethyl)-6-
(5-hydroxy-2-methoxyphenyl)-2,2,4- trimethyl-1,2-dihydroquinoline
(Reference Compound No. 3-2) ##STR00024## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.02 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H),
2.06 (s, 3H), 3.61 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J =
12.2 Hz, 1H), 5.38 (s, 1H), 5.99 (s, 1H), 6.33 (dd, J = 11.5, 2.4
Hz, 1H), 6.51 (td, J = 8.4, 2.4 Hz, 1H), 6.59 (d, J = 2.9 Hz, 1H),
6.61 (d, J = 8.3 Hz, 1H), 6.67 (dd, J = 8.8, 2.9 Hz, 1H), 6.75 (d,
J = 8.3 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 7.00-7.04 (m, 1H), 8.93
(s, 1H) 6-(4-Hydroxy-2-methoxyphenyl)-5-(2-
methyl-5-nitrophenoxymethyl)-2,2,4-trimethyl- 1,2-dihydroquinoline
(Reference Compound No. 3-3) ##STR00025## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.85 (s, 3H), 1.17 (s, 3H), 2.13 (s, 3H),
2.18 (s, 3H), 3.68 (s, 3H), 4.79 (d, J = 12.5 Hz, 1H), 5.30 (d, J
=12.5 Hz, 1H), 5.37 (s, 1H), 5.92 (s, 1H), 6.40 (dd, J = 8.2, 2.3
Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.74
(d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 2.3 Hz,
1H), 7.32 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 2.3 Hz, 1H), 9.50
(s, 1H) (6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-di- hydroquinoline
(Reference Compound No.3-4) ##STR00026## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.98 (s, 3H), 1.17 (s, 3H), 2.13 (s, 3H),
3.63 (s, 3H), 3.82 (s, 3H), 4.67 (d, J = 12.0 Hz, 1H), 5.24 (d, J =
12.0 Hz, 1H), 5.36 (s, 1H), 5.90 (s, 1H), 6.28 (dd, J = 8.3, 2.2
Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.71
(d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 9.2 Hz,
1H), 7.28 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 9.2, 2.8 Hz, 1H), 9.40
(s, 1H)
Example 1
6-(4-Benzoyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4--
trimethyl-1,2-dihydroquinoline (Compound No. 1-1)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.5 mg,
0.588 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL),
then triethylamine (19.7 .mu.L, 0.141 mmol) and benzoyl chloride
(8.2 .mu.L, 0.071 mmol) were added thereto. The reaction mixture
was stirred at room temperature for 30 minutes. The mixture was
diluted with ethyl acetate (100 mL). The mixture was washed with
water (100 mL) and saturated brine (50 mL) successively, dried over
anhydrous magnesium sulfate, and then the solvent was removed under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane-ethyl acetate) to give the titled
compound (26.7 mg) as a colorless solid. (Yield 63%)
TABLE-US-00013 ##STR00027## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H),
3.74 (s, 3H), 4.65 (d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H),
5.40 (s, 1H), 6.04 (s, 1H), 6.38 (dd, J = 11.5, 2.4 Hz, 1H), 6.54
(td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.82 (d, J =
8.2 Hz, 1H), 6.89 (dd, J = 8.2, 2.3 Hz, 1H), 7.03-7.06 (m, 1H),
7.05 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.62 (t, J =
7.4 Hz, 2H), 7.76 (t, J = 7.4 Hz, 1H), 8.15 (d, J = 7.4 Hz, 2H)
6-(4-t-Butoxycarbonylaminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphe-
noxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No.
1-2)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 30.2 mg,
0.070 mmol) and Boc-glycine (15.1 mg, 0.086 mmol) were dissolved in
N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (31.4
.mu.L, 0.18 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium
hexafluorophosphate (35.4 mg, 0.093 mmol) were added thereto, and
then the mixture was stirred at room temperature overnight. Ethyl
acetate (10 mL) was added to the reaction mixture, then the mixture
was washed with water (10 mL) and saturated brine (10 mL)
successively. The organic layer was dried over anhydrous magnesium
sulfate and the solvent was removed under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to give the titled compound (35.3 mg) as a
colorless amorphous product. (Yield 86%)
TABLE-US-00014 ##STR00028## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.15 (s, 3H), 1.40 (s, 9H), 2.01 (s, 3H),
2.07 (s, 3H), 3.71 (s, 3H), 3.96 (d, J = 6.0 Hz, 2H), 4.61 (d, J =
12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.04 (s,
1H), 6.34 (d, J = 11.5 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H),
6.63 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.3, 2.3 Hz, 1H), 6.78 (d,
J = 8.2 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 7.01-7.05 (m, 1H), 7.19
(d, J = 8.3 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H)
Using any compounds among Reference Compounds No. 3-1.about.3-4,
the following Compounds (No. 1-3.about.1-125) were obtained by a
method similar to that of Compound No. 1-1 or 1-2.
TABLE-US-00015 5-(5-Fluoro-2-methylphenoxymethyl)-6-
[2-methoxy-4-(4-methylbenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-3) ##STR00029##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.43 (s, 3H), 3.74 (s, 3H), 4.65
(d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.04
(s, 1H), 6.37 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4
Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.87
(dd, J = 8.2, 2.3 Hz, 1H), 7.02-7.06 (m, 1H), 7.03 (d, J = 2.3 Hz,
1H), 7.23 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 8.04 (d, J
= 8.2 Hz, 2H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-
[2-methoxy-4-(3-methylbenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-4) ##STR00030##
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.42 (s, 3H), 3.74 (s, 3H), 4.65
(d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03
(s, 1H), 6.38 (dd, J = 11.3, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4
Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.88
(dd, J = 8.2, 2.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.03 (d, J = 2.2 Hz,
1H), 7.23 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.57 (d, J
= 7.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-
[2-methoxy-4-(2-methylbenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-5) ##STR00031##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.61 (s, 3H), 3.75 (s, 3H), 4.66
(d, J = 12.1 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.04
(s, 1H), 6.38 (dd, J = 11.5, 2.5 Hz, 1H), 6.53 (td, J = 8.4, 2.5
Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.89
(dd, J = 8.2, 2.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.05 (d, J = 2.2 Hz,
1H), 7.24 (d, J = 8.2 Hz, 1H), 7.39-7.43 (m, 1H), 7.42 (d, J = 7.6
Hz, 1H), 7.56-7.60 (m, 1H), 8.09 (d, J = 8.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-
[2-methoxy-4-(4-methylbenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-6) ##STR00032##
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.88 (s, 3H), 4.65
(d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03
(s, 1H), 6.37 (dd, J = 11.3, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4
Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.86
(dd, J = 8.1, 2.1 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 7.03-7.06 (m,
1H), 7.13 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 1H) 8.10 (d, J
= 8.9 Hz, 2H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-
[2-methoxy-4-(3-methoxybenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-7) ##STR00033##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.86 (s, 3H), 4.65
(d, J = 12.0 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.05
(s, 1H), 6.38 (dd, J = 11.5, 2.5 Hz, 1H), 6.54 (td, J = 8.4, 2.5
Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.89
(dd, J = 8.2, 2.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.05 (d, J = 2.2 Hz,
1H), 7.24 (d, J = 8.2 Hz, 1H), 7.31-7.34 (m, 1H), 7.53 (t, J =7.9
Hz, 1H) 7.62 (dd, J = 2.4, 1.5 Hz, 1H), 7.72-7.75 (m, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-
methoxy-4-(2-methoxybenzoyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-8) ##STR00034##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s,
3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.88 (s, 3H), 4.65
(d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03
(s, 1H), 6.37 (dd, J = 11.4, 2.6 Hz, 1H), 6.53 (td, J = 8.3, 2.4
Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.84
(dd, J = 8.3, 2.2 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 7.02- 7.06 (m,
1H), 7.10 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.23 (d, J
= 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H)
6-[4-(4-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-9) ##STR00035## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s,
3H), 4.65 (d, J = 11.9 Hz, 1H), 5.10 (d, J = 11.9 Hz, 1H), 5.40 (s,
1H), 6.03 (s, 1H), 6.37 (dd, J = 11.5, 2.5 Hz, 1H), 6.53 (td, J =
8.4, 2.5 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz,
1H), 6.90 (dd, J = 8.2, 2.4 Hz, 1H), 7.03- 7.07 (m, 1H), 7.06 (d, J
= 2.4 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H),
8.15 (d, J = 8.6 Hz, 2H)
6-[4-(3-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-10) ##STR00036## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s,
3H), 4.65 (d, J = 11.9 Hz, 1H), 5.10 (d, J = 11.9 Hz, 1H), 5.40 (s,
1H), 6.04 (s, 1H), 6.38 (dd, J = 11.6, 2.4 Hz, 1H), 6.53 (td, J =
8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz,
1H), 6.92 (dd, J = 8.2, 2.2 Hz, 1H), 7.03- 7.06 (m, 1H), 7.09 (d, J
= 2.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H),
7.84 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 8.10 (dt, J = 7.9, 1.1 Hz,
1H), 8.12 (t, J = 2.0 Hz, 1H)
6-[4-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-11) ##STR00037## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.75 (s,
3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.40 (s,
1H), 6.05 (s, 1H), 6.38 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J =
8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz,
1H), 6.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.02- 7.06 (m, 1H), 7.07 (d, J
= 2.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.54- 7.58 (m, 1H),
7.67-7.69 (m, 2H), 8.10-8.12 (m, 1H)
6-(4-Cyclohexylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No.1-12) ##STR00038## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.15 (s, 3H), 1.17-1.72 (m, 10H), 1.99-2.01
(m, 1H), 2.01 (s, 3H), 2.07 (s, 3H), 3.71 (s, 3H), 4.61 (d, J =
12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.03 (s,
1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz,
1H), 6.63 (d, J = 8.3 Hz, 1H), 6.70 (dd, J = 8.3, 2.3 Hz, 1H), 6.78
(d, J = 8.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 7.01-7.05 (m, 1H),
7.17 (d, J = 8.3 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-
3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-13) ##STR00039## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.38 (dd, J = 11.4, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-
7.06 (m, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H),
7.66 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 8.48 (dt, J = 8.0, 2.0 Hz,
1H), 8.91 (dd, J = 4.9, 2.0 Hz, 1H), 9.27 (dd, J = 2.0, 0.8 Hz, 1H)
6-(4-Butyryloxy-2-methoxyphenyl)-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-14) ##STR00040## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
0.98 (t, J = 7.3 Hz, 3H), 1.05 (s, 3H), 1.15 (s, 3H), 1.64-1.70 (m,
2H), 2.01 (s, 3H), 2.07 (s, 3H), 2.55 (t, J = 7.3 Hz, 2H), 3.71 (s,
3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.2 Hz, 1H), 5.39 (s,
1H), 6.03 (s, 1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J =
8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.2, 2.2
Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H),
7.01-7.05 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H)
6-(4-Acetoxy-2-methoxyphenyl)-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-15) ##STR00041## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 2.26 (s,
3H), 3.71 (s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.2 Hz,
1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.33 (dd, J = 11.6, 2.4 Hz, 1H),
6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.72 (dd,
J = 8.2, 2.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 2.1
Hz, 1H), 7.02-7.05 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-
4-propionyloxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-16) ##STR00042## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H), 1.15
(s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 3.71
(s, 3H), 4.61 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 5.39
(s, 1H), 6.03 (s, 1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J
= 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.72 (dd, J = 8.1,
2.2 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H),
7.01- 7.05 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H)
6-(4-Acryloyloxy-2-methoxyphenyl)-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-17) ##STR00043## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.
1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 3.75 (s,
3H), 4.75 (d, J = 11.9 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 5.45 (s,
1H), 6.03 (d, J = 10.4 Hz, 1H), 6.19 (dd, J = 11.0, 2.4 Hz, 1H),
6.34 (dd, J = 17.7, 10.4 Hz, 1H), 6.42 (td, J = 8.3, 2.4 Hz, 1H),
6.58 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 17.7 Hz, 1H), 6.75 (d, J =
2.1 Hz, 1H), 6.78 (dd, J = 8.2, 2.1 Hz, 1H), 6.91 (d, J = 8.4 Hz,
1H), 6.92-6.95 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-
(thiophen-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-18) ##STR00044## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s,
3H), 2.08 (s, 3H), 3.73 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.09
(d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.37 (dd, J =
11.3, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2
Hz, 1H), 6.81 (d, J = 8.2, 1H), 6.86 (dd, J = 8.2, 2.2 Hz, 1H),
7.01 (d, J = 2.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.22 (d, J = 8.2 Hz,
1H), 7.62 (dd, J = 5.0, 1.2 Hz, 1H), 7.75 (dd, J = 5.0, 3.0 Hz,
1H), 8.60 (dd, J = 3.0, 1.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(furan-2-
ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-19) ##STR00045## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s,
3H), 2.08 (s, 3H), 3.73 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.09
(d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.37 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2
Hz, 1H), 6.80 (d, J = 8.2, 1H), 6.81 (dd, J = 3.6, 1.8 Hz, 1H),
6.86 (dd, J = 8.2, 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 7.02-7.05
(m, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 3.6 Hz, 1H), 8.11
(d, J = 1.8 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-isobutyryloxy-2-
methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No.
1-20) ##STR00046## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.05
(s, 3H), 1.15 (s, 3H), 1.24 (d, J = 7.0 Hz, 6H), 2.01 (s, 3H), 2.07
(s, 3H), 2.81 (sept, J = 7.0 Hz, 1H), 3.72 (s, 3H), 4.61 (d, J =
12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.03 (s,
1H), 6.35 (dd, J = 11.5, 2.5 Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz,
1H), 6.63 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 6.78
(d, J = 8.3 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 7.02- 7.05 (m, 1H),
7.18 (d, J = 8.3 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-
phenylacetoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-21) ##STR00047## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 3.71 (s,
3H), 3.96 (s, 2H), 4.60 (d, J = 12.2, 1H), 5.06 (d, J = 12.2 Hz,
1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.33 (dd, J = 11.5, 2.5 Hz, 1H),
6.52 (td, J = 8.4, 2.5 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.71 (dd,
J = 8.1, 2.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.2
Hz, 1H), 7.01-7.04 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.28-7.32 (m,
1H), 7.35- 7.40 (m, 4H)
6-[5-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-22) ##STR00048## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.10 (s, 3H), 1.14 (s, 3H), 2.00 (s, 3H), 2.06 (s, 3H), 3.76 (s,
3H), 4.64 (d, J = 12.0 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.40 (s,
1H), 6.08 (s, 1H), 6.44 (dd, J = 11.2, 2.4 Hz, 1H), 6.52 (td, J =
8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz,
1H), 6.98-7.02 (m, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.13 (d, J = 8.9
Hz, 1H), 7.24 (dd, J = 8.9, 2.9 Hz, 1H), 7.54 (ddd, J = 8.1, 4.7,
3.1 Hz, 1H), 7.65- 7.66 (m, 2H), 7.96-7.98 (m, 1H)
6-[5-(3-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-23) ##STR00049## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.12 (s, 3H), 1.13 (s, 3H), 1.99 (s, 3H), 2.06 (s, 3H), 3.76 (s,
3H), 4.60 (d, J = 12.5 Hz, 1H), 5.09 (d, J = 12.5 Hz, 1H), 5.40 (s,
1H), 6.07 (s, 1H), 6.46 (dd, J = 11.6, 2.5 Hz, 1H), 6.53 (td, J =
8.3, 2.5 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz,
1H), 6.96-6.99 (m, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.12 (d, J = 9.1
Hz, 1H), 7.23 (dd, J = 9.1, 2.9 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H),
7.82 (d, J = 8.1 Hz, 1H), 8.00-8.01 (m, 2H)
6-[5-(4-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-24) ##STR00050## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.11 (s, 3H), 1.13 (s, 3H), 1.98 (s, 3H), 2.06 (s, 3H), 3.76 (s,
3H), 4.61 (d, J = 11.9 Hz, 1H), 5.09 (d, J = 11.9 Hz, 1H), 5.40 (s,
1H), 6.07 (s, 1H), 6.45 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J =
8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz,
1H), 6.96-7.00 (m, 1H), 7.09 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 9.0
Hz, 1H), 7.22 (dd, J = 9.0, 2.8 Hz, 1H), 7.68 (dt, J = 9.1, 2.2 Hz,
2H), 8.05 (dt, J = 9.1, 2.2 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-(thiophen-
3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-25) ##STR00051## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.10 (s, 3H), 1.13 (s, 3H), 1.98 (s, 3H),
2.06 (s, 3H), 3.75 (s, 3H), 4.63 (d, J = 11.8 Hz, 1H), 5.09 (d, J =
11.8 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.43 (dd, J = 11.3, 2.4
Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.84 (d, J = 8.2 Hz, 1H), 6.97-7.00 (m, 1H), 7.05 (d, J = 2.9 Hz,
1H), 7.10 (d, J = 8.9 Hz, 1H), 7.18 (dd,
J = 8.9, 2.9 Hz, 1H), 7.54 (dd, J = 5.1, 1.2 Hz, 1H), 7.73 (dd, J =
5.1, 3.0 Hz, 1H), 8.51 (dd, J = 3.0, 1.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[5-(furan-2-
ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-26) ##STR00052## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.10 (s, 3H), 1.13 (s, 3H), 1.99 (s,
3H), 2.06 (s, 3H), 3.75 (s, 3H), 4.64 (d, J = 12.3 Hz, 1H), 5.08
(d, J = 12.3 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.42 (dd, J =
11.5, 2.5 Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 8.3
Hz, 1H), 6.79 (dd, J = 3.6, 1.7 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H),
6.97-7.00 (m, 1H), 7.06 (d, J = 2.9 Hz, 1H), 7.10 (d, J = 8.9 Hz,
1H), 7.19 (dd, J = 8.9, 2.9 Hz, 1H), 7.48 (dd, J = 3.6, 0.7 Hz,
1H), 8.08 (dd, J = 1.7, 0.7 Hz, 1H)
5-(5-Fluoro-2-methylphenoxylmethyl)-6-(2-methoxy-5-
propionyloxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-27) ##STR00053## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.09 (t, J = 7.5 Hz, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 2.01 (s, 3H),
2.06 (s, 3H), 2.49-2.53 (m, 2H), 3.72 (s, 3H), 4.60 (d, J = 11.9
Hz, 1H), 5.07 (d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H),
6.40 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H),
6.64 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.92 (d, J =
2.4 Hz, 1H), 7.02- 7.06 (m, 3H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-
(pyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-28) ##STR00054## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.12 (s, 3H), 1.13 (s, 3H), 1.98 (s,
3H), 2.06 (s, 3H), 3.76 (s, 3H), 4.62 (d, J = 11.9 Hz, 1H), 5.09
(d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.08 (s, 1H), 6.46 (dd, J =
11.5, 2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.94-6.98 (m, 1H), 7.13 (d, J =
2.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.25 (dd, J = 9.0, 2.9 Hz,
1H), 7.65 (ddd, J = 8.1, 4.9, 1.1 Hz, 1H), 8.38 (dt, J = 8.1, 1.9
Hz, 1H), 8.89 (dd, J = 4.9, 1.9 Hz, 1H), 9.18 (t, J = 1.1 Hz, 1H)
6-(5-Butyryloxy-2-methoxyphenyl)-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-29) ##STR00055## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.94 (t, J = 7.3 Hz, 3H), 1.09 (s, 3H), 1.14
(s, 3H), 1.57-1.66 (m, 2H), 2.01 (s, 3H), 2.06 (s, 3H), 2.49-2.52
(m, 2H), 3.72 (s, 3H), 4.59 (d, J = 12.0 Hz, 1H), 5.07 (d, J = 12.0
Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.40 (dd, J = 11.5, 2.4 Hz,
1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.80
(d, J = 8.3 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.01-7.07 (m, 3H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(5-
isobutyryloxy-2-methoxyphenyl)-2,2,4-trimethyl-
1,2-dihydroquinoline (Compound No. 1-30) ##STR00056## .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. 1.08 (s, 3H), 1.14 (s, 3H), 1.17
(d, J = 7.1 Hz, 6H), 2.01 (s, 3H), 2.06 (s, 3H), 2.73 (sept, J =
7.1 Hz, 1H), 3.72 (s, 3H), 4.57 (d, J = 11.9 Hz, 1H), 5.08 (d, J =
11.9 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.40 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H),
6.80 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 7.01-7.07 (m,
3H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiophen-
2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-31) ##STR00057## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.09 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.37 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H),
6.81 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.03 (d,
J = 2.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.32
(dd, J = 5.0, 3.9 Hz, 1H), 8.03 (dd, J = 3.9, 1.3 Hz, 1H), 8.10
(dd, J = 5.0, 1.3 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-
phenylacetoxyphenyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-32) ##STR00058## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.09 (s, 3H), 1.13 (s, 3H), 1.99 (s, 3H),
2.05 (s, 3H), 3.72 (s, 3H), 3.88 (s, 2H), 4.58 (d, J = 11.9 Hz,
1H), 5.06 (d, J = 11.9 Hz, 1H), 5.39 (s, 1H), 6.06 (s, 1H), 6.39
(dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.5, 2.4 Hz, 1H), 6.63
(d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 2.0 Hz,
1H), 7.01-7.05 (m, 3H), 7.28-7.38 (m, 5H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-
phenylpropionyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-33) ##STR00059## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H),
2.06 (s, 3H), 2.88-2.92 (m, 2H), 2.96- 3.00 (m, 2H), 3.69 (s, 3H),
4.60 (d, J = 12.1 Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H),
6.03 (s, 1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J = 8.4,
2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.64 (dd, J = 8.1, 2.2 Hz,
1H), 6.73 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 7.01-7.05
(m, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.20- 7.24 (m, 1H), 7.29-7.34
(m, 4H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(furan-3-
ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-34) ##STR00060## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s,
3H), 2.07 (s, 3H), 3.73 (s, 3H), 4.62 (d, J = 12.2 Hz, 1H), 5.08
(d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.37 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2
Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H),
6.94 (dd, J = 1.7, 0.9 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.92 (t, J = 1.7 Hz, 1H), 8.64
(dd, J = 1.7, 0.9 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-
(pyridin-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-35) ##STR00061## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 4.66 (d, J = 12.2 Hz, 1H), 5.10
(d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.38 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.2 Hz, 1H),
7.03-7.06 (m, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.2 Hz,
1H), 7.74 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 8.09 (td, J = 7.7, 1.7
Hz, 1H), 8.25 (dt, J = 7.7, 1.1 Hz, 1H), 8.82 (ddd, J = 4.7, 1.7,
1.1 Hz, 1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-
methoxy-5-(thiophen-2-ylcarbonyloxy)phenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-36) ##STR00062##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.11 (s, 3H), 1.13 (s,
3H), 1.99 (s, 3H), 2.06 (s, 3H), 3.75 (s, 3H), 4.61 (d, J = 12.4
Hz, 1H), 5.09 (d, J = 12.4 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H),
6.44 (dd, J = 11.4, 2.5 Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz, 1H),
6.64 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.96-7.01 (m,
1H), 7.07 (d, J = 2.9 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 7.20 (dd,
J = 8.9, 2.9 Hz, 1H), 7.30 (dd, J = 5.0, 3.8 Hz, 1H), 7.94 (dd, J =
3.8, 1.3 Hz, 1H), 8.07 (dd, J = 5.0, 1.3 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[5-
(furan-3-ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-
trimethyl-1,2-dihydroquinoline (Compound No. 1-37) ##STR00063##
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.10 (s, 3H), 1.13 (s,
3H), 1.99 (s, 3H), 2.06 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 12.4
Hz, 1H), 5.08 (d, J = 12.4 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H),
6.42 (dd, J = 11.5, 2.5 Hz, 1H), 6.53 (td, J = 8.5, 2.5 Hz, 1H),
6.64 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.87 (dd, J =
1.7, 0.9 Hz, 1H), 6.98- 7.01 (m, 1H), 7.04 (d, J = 2.9 Hz, 1H),
7.10 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 9.0, 2.9 Hz, 1H), 7.89 (t,
J = 1.7 Hz, 1H), 8.55 (dd, J = 1.7, 0.9 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
nitrobenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-38) ##STR00064## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.75 (s, 3H), 4.64 (d, J = 12.2 Hz, 1H), 5.09 (d, J
=12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.4, 2.3
Hz, 1H), 6.53 (td, J = 8.5, 2.3 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
6.81 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.3, 2.2 Hz, 1H), 7.02 (d,
J = 2.2 Hz, 1H), 7.02- 7.06 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.92
(td, J = 7.7, 1.4 Hz, 1H), 7.96 (td, J = 7.7, 1.4 Hz, 1H), 8.13
(dd, J = 7.7, 1.4 Hz, 1H), 8.19 (dd, J = 7.7, 1.4 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-
nitrobenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-39) ##STR00065## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.75 (s, 3H), 4.65 (d, J = 12.1 Hz, 1H), 5.11 (d, J
=12.1 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.39 (dd, J = 11.5, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.3, 2.2 Hz, 1H), 7.03-7.07
(m, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.93
(t, J = 7.9 Hz, 1H), 8.54- 8.56 (m, 1H), 8.58-8.61 (m, 1H), 8.81
(t, J = 2.0 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
nitrobenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-40) ##STR00066## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.65 (d, J = 12.1 Hz, 1H), 5.10 (d, J
=12.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.4, 2.3
Hz, 1H), 6.54 (td, J = 8.4, 2.3 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.3, 2.2 Hz, 1H), 7.03-7.06
(m, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 8.38
(d, J = 9.0 Hz, 2H), 8.43 (d, J = 9.0 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-
(2-trifluoromethylbenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-41) ##STR00067## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.02 (s,
3H), 2.08 (s, 3H), 3.76 (s, 3H), 4.65 (d, J = 12.1 Hz, 1H), 5.10
(d, J =12.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J =
11.4, 2.4 Hz, 1H), 6.53 (td, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 8.3
Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.2, 2.3 Hz, 1H),
7.02- 7.06 (m, 1H), 7.04 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.2 Hz,
1H), 7.86-7.93 (m, 2H), 7.97-8.00 (m, 1H), 8.15 (d, J = 7.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-
methoxyacetoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-42) ##STR00068## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H),
2.07 (s, 3H), 3.40 (s, 3H), 3.72 (s, 3H), 4.33 (s, 2H), 4.61 (d, J
= 12.2 Hz, 1H), 5.07 (d, J =12.2 Hz, 1H), 5.39 (s, 1H), 6.04 (s,
1H), 6.35 (dd, J = 11.5, 2.5 Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz,
1H), 6.63 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.1, 2.1 Hz, 1H), 6.78
(d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 7.01-7.05 (m, 1H),
7.19 (d, J = 8.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-4-
ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-43) ##STR00069## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.10 (d, J
=12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.38 (dd, J = 11.3, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
6.81 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.4 Hz, 1H), 7.03-7.06
(m, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 8.02
(d, J = 6.0 Hz, 2H), 8.89 (d, J = 6.0 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-
(pyridin-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-44) ##STR00070## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.10 (s, 3H), 1.13 (s, 3H), 1.98 (s,
3H), 2.06 (s, 3H), 3.76 (s, 3H), 4.67 (d, J = 12.0 Hz, 1H), 5.09
(d, J =12.0 Hz, 1H), 5.40 (s, 1H), 6.08 (s, 1H), 6.43 (dd, J =
11.6, 2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3
Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.95-6.99 (m, 1H), 7.11 (d, J =
2.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.23 (dd, J = 9.0, 2.9 Hz,
1H), 7.73 (ddd, J = 7.7, 4.8, 1.1 Hz, 1H), 8.07 (td, J = 7.7, 1.7
Hz, 1H), 8.15 (dt, J = 7.7, 1.1 Hz, 1H), 8.80 (ddd, J = 4.8, 1.7,
1.1 Hz, 1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-5-
(pyridin-4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-45) ##STR00071## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.12 (s, 3H), 1.13 (s, 3H), 1.98 (s,
3H), 2.06 (s, 3H), 3.76 (s, 3H), 4.61 (d, J = 11.8 Hz, 1H), 5.09
(d, J =11.8 Hz, 1H), 5.40 (s, 1H), 6.09 (s, 1H), 6.45 (dd, J =
11.4, 2.4 Hz, 1H), 6.53 (td, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 8.3
Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.96-6.99 (m, 1H), 7.13 (d, J =
2.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.26 (dd, J = 9.0, 2.9 Hz,
1H), 7.92 (d, J = 6.1 Hz, 2H), 8.88 (d, J = 6.1 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
naphtylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-46) ##STR00072## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.04 (s, 3H),
2.09 (s, 3H), 3.75 (s, 3H), 4.66 (d, J = 12.1 Hz, 1H), 5.11 (d, J
=12.1 Hz, 1H), 5.41 (s, 1H), 6.05 (s, 1H), 6.40 (dd, J = 11.5, 2.4
Hz, 1H), 6.55 (td, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H),
6.84 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.4 Hz, 1H), 7.04-7.07
(m, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.65-
7.69 (m, 1H), 7.71-7.75 (m, 1H), 8.08 (d, J = 8.3 Hz, 1H),
8.12-8.15 (m, 2H), 8.22 (d, J = 8.0 Hz, 1H), 8.87 (s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(1-
naphtylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-47) ##STR00073## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.19 (s, 3H), 2.05 (s, 3H),
2.09 (s, 3H), 3.77 (s, 3H), 4.68 (d, J = 12.4 Hz, 1H), 5.13 (d, J
=12.4 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.40 (dd, J = 11.7, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H),
6.84 (d, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.2, 2.1 Hz, 1H), 7.04-
7.07 (m, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H),
7.64-7.74 (m, 3H), 8.11 (d, J = 7.3 Hz, 1H), 8.31 (d, J = 8.1 Hz,
1H), 8.47 (d, J = 7.3 Hz, 1H), 8.86 (d, J = 8.3 Hz, 1H)
6-(5-Benzoyloxy-2-methoxyphenyl)-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-48) ##STR00074## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.16 (s, 3H), 1.23 (s, 3H), 2.05 (s, 3H), 2.15 (s, 3H),
3.77 (s, 3H), 3.87 (br s, 1H), 4.77 (d, J = 11.9 Hz, 1H), 5.12 (d,
J = 11.9 Hz, 1H), 5.46 (s, 1H), 6.27 (dd, J = 11.3, 2.4 Hz, 1H),
6.43 (td, J = 8.2, 2.4 Hz, 1H),
6.59 (d, J = 8.2 Hz, 1H), 6.89-6.92 (m, 1H), 6.96 (d, J = 8.8 Hz,
1H), 6.97 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 3.1 Hz, 1H), 7.17 (dd,
J = 8.8, 3.1 Hz, 1H), 7.50 (t, J = 7. 8 Hz, 2H), 7.62 (t, J = 7.8
Hz, 1H), 8.16 (d, J = 7.8 Hz, 2H)
6-[4-(3-Dimethylaminobenzoyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-49) ##STR00075## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.13 (s, 3H), 1.24 (s, 3H), 2.08 (s, 3H), 2.16 (s, 3H),
3.03 (s, 6H), 3.77 (s, 3H), 4.78 (d, J = 12.1 Hz, 1H), 5.13 (d, J =
12.1 Hz, 1H), 5.46 (s, 1H), 6.22 (dd, J = 11.2, 2.4 Hz, 1H), 6.43
(td, J = 8.3, 2.4 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.84 (d, J =
2.2 Hz, 1H), 6.86 (dd, J = 8.1, 2.2 Hz, 1H), 6.94 (d, J = 8.2 Hz,
1H), 6.92-6.96 (m, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.1
Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.52-7.57 (m, 2H)
6-[4-(2-Acetoxybenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-50) ##STR00076## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.
1.13 (s, 3H), 1.23 (s, 3H), 2.08 (s, 3H), 2.17 (s, 3H), 2.32 (s,
3H), 3.76 (s, 3H), 4.75 (d, J = 11.9 Hz, 1H), 5.12 (d, J = 11.9 Hz,
1H), 5.46 (s, 1H), 6.21 (dd, J = 11.0, 2.4 Hz, 1H), 6.43 (td, J =
8.4, 2.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 2.1 Hz,
1H), 6.81 (dd, J = 8.1, 2.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H),
6.93-6.95 (m, 1H), 7.19 (dd, J = 7.9, 1.4 Hz, 1H), 7.29 (d, J = 8.1
Hz, 1H), 7.40 (td, J = 7.9, 1.4 Hz, 1H), 7.65 (td, J = 7.9, 1.4 Hz,
1H), 8.24 (dd, J = 7.9, 1.4 Hz, 1H)
6-[4-(1-t-Butoxycarbonylpiperidin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-51) ##STR00077## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 1.53-1.62 (m,
2H), 1.95-1.96 (m, 2H), 2.01 (s, 3H), 2.07 (s, 3H), 2.81-2.84 (m,
1H), 2.91- 2.93 (m 2H), 3.72 (s, 3H), 3.89-3.92 (m, 2H), 4.61 (d, J
= 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.03 (s,
1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz,
1H), 6.63 (d, J = 8.1 Hz, 1H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 6.78
(d, J = 8.1 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 7.01-7.05 (m, 1H),
7.18 (d, J = 8.3 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
methylthiobenzoyloxy)phenyl]-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-52) ##STR00078## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 2.47 (s, 3H), 3.74 (s, 3H), 4.66 (d, J = 12.2 Hz,
1H), 5.11 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.38
(dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.65
(d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.0,
2.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 7.03- 7.06 (m, 1H), 7.24 (d,
J = 8.0 Hz, 1H), 7.31-7.35 (m, 1H), 7.47 (d, J = 7.9 Hz, 1H),
7.66-7.69 (m, 1H), 8.19 (dd, J = 7.6, 1.5 Hz, 1H)
6-[4-(1-t-Butoxycarbonylimidazol-4-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-53) ##STR00079## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 1.61 (s, 9H),
2.02 (s, 3H), 2.08 (s, 3H), 3.73 (s, 3H), 4.63 (d, J = 12.1 Hz,
1H), 5.09 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37
(dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64
(d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.3,
2.2 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 7.02- 7.06 (m, 1H), 7.22 (d,
J = 8.3 Hz, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.41 (d, J = 1.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-
4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-54) ##STR00080## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.10 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37 (dd, J = 11.2, 2.5
Hz, 1H), 6.53 (td, J = 8.4, 2.5 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.89 (dd, J = 8.3, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 8.88
(d, J = 1.9 Hz, 1H), 9.28 (d, J = 1.9 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiazol-5-
ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-55) ##STR00081## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 12.2 Hz, 1H), 5.09 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.2, 2.5
Hz, 1H), 6.53 (td, J = 8.5, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.81 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 8.76
(d, J = 0.7 Hz, 1H), 9.49 (d, J = 0.7 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(oxazol-
4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-56) ##STR00082## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.08 (s, 3H), 3.73 (s, 3H), 4.63 (d, J = 12.4 Hz, 1H), 5.09 (d, J =
12.4 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.37 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.81 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.2, 2.3 Hz, 1H), 7.01 (d,
J = 2.3 Hz, 1H), 7.02-7.06 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H), 8.67
(d, J = 1.0 Hz, 1H), 9.14 (d, J = 1.0 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-
methylthiophen-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-57) ##STR00083## .sup.1H-NMR (400
MHz, Solv. DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.02
(s, 3H), 2.07 (s, 3H), 2.57 (s, 3H), 3.74 (s, 3H), 4.63 (d, J =
12.1 Hz, 1H), 5.09 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s,
1H), 6.37 (dd, J = 11.4, 2.5 Hz, 1H), 6.53 (td, J = 8.4, 2.5 Hz,
1H), 6.64 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.85 (dd,
J = 8.3, 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 7.02-7.06 (m, 2H),
7.22 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 3.4 Hz, 1H)
6-[4-(3-Acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-58) ##STR00084## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.68 (s,
3H), 3.75 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 Hz,
1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.39 (dd, J = 11.3, 2.4 Hz, 1H),
6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.82 (d,
J = 8.1 Hz, 1H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 7.03- 7.06 (m,
1H), 7.09 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.79 (t, J
= 7.9 Hz, 1H), 8.32 (dt, J = 7.9, 1.5 Hz, 1H), 8.38 (dt, J = 7.9,
1.5 Hz, 1H), 8.68 (t, J =1.5 Hz, 1H)
6-[4-(2-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-59) ##STR00085## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s,
3H), 4.65 (d, J = 12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s,
1H), 6.05 (s, 1H), 6.38 (dd, J = 11.4, 2.4 Hz, 1H), 6.53 (td, J =
8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz,
1H), 6.90 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.06 (d, J
= 2.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.41-7.47 (m, 2H),
7.76-7.81 (m, 1H), 8.12 (td, J = 7.8, 1.7 Hz, 1H)
6-[4-(3-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-60) ##STR00086## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s,
3H), 4.64 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.40 (s,
1H), 6.06 (s, 1H), 6.38 (dd, J = 11.4, 2.5 Hz, 1H), 6.54 (td, J =
8.2, 2.5 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz,
1H), 6.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.02- 7.06 (m, 1H), 7.08 (d, J
= 2.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.63 (tdd, J = 8.5, 2.6,
1.2 Hz, 1H), 7.66-7.71 (m, 1H), 7.88- 7.91 (m, 1H), 8.00 (dt, J =
7.5, 1.4 Hz, 1H)
6-[4-(4-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-61) ##STR00087## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 3.74 (s,
3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.40 (s,
1H), 6.05 (s, 1H), 6.38 (dd, J = 11.3, 2.4 Hz, 1H), 6.54 (td, J =
8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz,
1H), 6.89 (dd, J = 8.1, 2.1 Hz, 1H), 7.03- 7.06 (m, 1H), 7.06 (d, J
= 2.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.44-7.47 (m, 2H),
8.20-8.23 (m, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-methylfuran-
2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-62) ##STR00088## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 2.42 (s, 3H), 3.73 (s, 3H), 4.63 (d, J = 12.0 Hz,
1H), 5.08 (d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.37
(dd, J = 11.5, 2.4 Hz, 1H), 6.45 (d, J = 3.4, Hz, 1H), 6.53 (td, J
= 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz,
1H), 6.84 (dd, J = 8.3, 2.3 Hz, 1H) 6.98 (d, J = 2.3 Hz, 1H),
7.02-7.06 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 3.4 Hz,
1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
methylpyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-63) ##STR00089## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 2.80 (s, 3H), 3.75 (s, 3H), 4.65 (d, J = 12.1
Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H),
6.38 (dd, J = 11.2, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H),
6.65 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.92 (dd, J =
8.2, 2.3 Hz, 1H) 7.03-7.06 (m, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.47
(dd, J = 7.9, 4.7 Hz, 1H), 8.45 (dd, J = 7.9, 1.7 Hz, 1H), 8.72
(dd, J = 4.7, 1.7 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyridin-3-
ylacetoxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-64) ##STR00090## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 3.71 (s,
3H), 4.05 (s, 2H), 4.60 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz,
1H), 5.39 (s, 1H), 6.04 (s, 1H), 6.34 (dd, J = 11.5, 2.4 Hz, 1H),
6.52 (td, J = 8.5, 2.4 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.75 (dd,
J = 8.2, 2.3 Hz, 1H) 6.78 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 2.3 Hz,
1H), 7.01-7.05 (m, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.40 (dd, J =
7.8, 4.8 Hz, 1H), 7.47 (dt, J = 7.8, 2.0 Hz, 1H), 8.50 (dd, J =
4.8, 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-methylthiophen-
2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-65) ##STR00091## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 2.56 (s, 3H), 3.74 (s, 3H), 4.65 (d, J = 12.1 Hz,
1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.37
(dd, J = 11.5, 2.5 Hz, 1H), 6.53 (td, J = 8.4, 2.5 Hz, 1H), 6.64
(d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H) 6.85 (dd, J = 8.2 ,
2.2 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.17 (d,
J = 5.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxylmethyl)-6-[2-methoxy-4-(4-
methylthiophen-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-66) ##STR00092## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 2.30 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.4
Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 5.41 (s, 1H), 6.05 (s, 1H),
6.38 (dd, J = 11.3, 2.5 Hz, 1H), 6.54 (td, J = 8.5, 2.5 Hz, 1H),
6.65 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.87 (dd, J =
8.2 , 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 7.04-7.07 (m, 1H),
7.23 (d, J = 8.2 Hz, 1H), 7.69-7.70 (m, 1H), 7.87 (d, J = 1.2 Hz,
1H) 6-[4-(4-Acetylbenzoyloxy)-2-methoxyphenyl]-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-67) ##STR00093## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.67 (s,
3H), 3.74 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz,
1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.5, 2.4 Hz, 1H),
6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.82 (d,
J = 8.2 Hz, 1H) 6.92 (dd, J = 8.3, 2.2 Hz, 1H), 7.03-7.07 (m, 1H),
7.09 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 8.14-8.17 (m,
2H), 8.25- 8.28 (m, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-
methoxycarbonylbenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-68) ##STR00094## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 4.65 (d, J = 12.2
Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H),
6.39 (dd, J = 11.5, 2.4 Hz, 1H), 6.54 (td, J = 8.3, 2.4 Hz, 1H),
6.65 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H) 6.93 (dd, J =
8.2, 2.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.25
(d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 8.31 (dt, J = 7.9,
1.6 Hz, 1H), 8.40 (dt, J = 7.9, 1.6 Hz, 1H), 8.66 (t, J = 1.6 Hz,
1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(6-
methylpyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-69) ##STR00095## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 2.61 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.2
Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H),
6.38 (dd, J = 11.4, 2.4 Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H),
6.65 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.91 (dd, J =
8.1, 2.2 Hz, 1H), 7.03- 7.06 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H),
7.24 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 8.35 (dd, J =
8.1, 2.2 Hz, 1H), 9.14 (d, J = 2.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methylpyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-70) ##STR00096## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.04 (s,
3H), 2.09 (s, 3H), 2.64 (s, 3H), 3.76 (s, 3H), 4.66 (d, J = 12.2
Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 5.41 (s, 1H), 6.05 (s, 1H),
6.39 (dd, J = 11.3, 2.4 Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H),
6.66 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.95 (dd, J =
8.0, 2.2 Hz, 1H), 7.04- 7.07 (m, 1H), 7.12 (d, J = 2.2 Hz, 1H),
7.26 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 5.1 Hz, 1H), 8.69 (d, J =
5.1 Hz, 1H), 9.19 (s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-
methylfuran-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-71) ##STR00097## .sup.1H-NMR (400
MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H), 2.08 (s, 3H),
2.38 (s, 3H), 3.73 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.10 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37 (dd, J = 11.4, 2.5
Hz, 1H), 6.53 (td, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.70 (d, J = 1.7 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.86 (dd, J =
8.3, 2.2 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 7.02- 7.06 (m, 1H),
7.22 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H)
6-(4-t-Butylcarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-2-
methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-72) ##STR00098## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 3H), 1.15 (s, 3H), 1.31 (s, 9H), 2.02 (s, 3H), 2.06 (s,
3H), 3.73 (s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.2 Hz,
1H), 5.39 (s, 1H), 6.03 (s, 1H), 6.35 (dd, J = 11.3, 2.4 Hz, 1H),
6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.69 (dd,
J = 8.1, 2.3 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.3
Hz, 1H), 7.02-7.05 (m, 1H), 7.18 (d, J = 8.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
trifluoromethoxybenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-73) ##STR00099## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.65 (d, J = 12.1 Hz, 1H), 5.10 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.5, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
6.82 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-
7.06 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H),
7.59-7.62 (m, 2H), 8.26-8.29 (m, 2H)
6-[4-(Benzothiophen-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-74) ##STR00100## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.76 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.11 (d, J =
12.2 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.39 (dd, J = 11.5, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.94 (dd, J = 8.2, 2.2 Hz, 1H), 7.03-
7.07 (m, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H),
7.51-7.55 (m, 1H), 7.58-7.62 (m, 1H), 8.10-8.12 (m, 1H), 8.13- 8.15
(m, 1H), 8.46 (s, 1H)
6-[4-(Benzothiophen-3-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-75) ##STR00101## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.04 (s, 3H),
2.09 (s, 3H), 3.76 (s, 3H), 4.67 (d, J = 12.2 Hz, 1H), 5.12 (d, J =
12.2 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.40 (dd, J = 11.2, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H),
6.83 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 2.3 Hz, 1H), 7.03-
7.07 (m, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H),
7.50-7.54 (m, 1H), 7.55-7.59 (m, 1H), 8.16-8.18 (m, 1H), 8.49- 8.52
(m, 1H), 9.03 (s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
methoxycarbonylbenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-76) ##STR00102## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 4.64 (d, J = 12.2
Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H),
6.38 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.3, 2.4 Hz, 1H),
6.62 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.89 (dd, J =
8.2, 2.2 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.26
(d, J = 8.2 Hz, 1H), 7.75-7.80 (m, 2H), 7.85-7.87 (m, 1H),
7.96-7.99 (m, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methoxycarbonylbenzoyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-77) ##STR00103## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 4.65 (d, J = 12.2
Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H),
6.38 (dd, J = 11.5, 2.4 Hz, 1H), 6.54 (td, J = 8.3, 2.4 Hz, 1H),
6.65 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.93 (dd, J =
8.2, 2.2 Hz, 1H), 7.03-7.07 (m, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.25
(d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.6 Hz,
2H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(pyrimidin-
5-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-78) ##STR00104## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.1 Hz, 1H), 5.09 (d, J =
12.1 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.39 (dd, J = 11.3, 2.5
Hz, 1H), 6.54 (td, J = 8.3, 2.5 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
6.82 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.2 Hz, 1H), 7.03-7.06
(m, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 9.44
(s, 2H), 9.51 (s, 1H)
6-[4-(3-Chlorothiophen-2-ylcarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-79) ##STR00105## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.02 (s,
3H), 2.07 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.3 Hz, 1H), 5.10
(d, J = 12.3 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37 (dd, J =
11.4, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2
Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.3 Hz, 1H),
7.02-7.06 (m, 1H), 7.04 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 8.2 Hz,
1H), 7.36 (d, J = 5.1 Hz, 1H), 8.15 (d, J = 5.1 Hz, 1H)
6-[4-(5-Chlorothiophen-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-80) ##STR00106## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.73 (s, 3H), 4.62 (d, J = 12.1 Hz, 1H), 5.08 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.80 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.1, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.39
(d, J = 4.2 Hz, 1H), 7.93 (d, J = 4.2 Hz, 1H)
6-[4-(5-Bromothiophen-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-81) ##STR00107## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.73 (s, 3H), 4.63 (d, J = 12.2 Hz, 1H), 5.09 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.37 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.80 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.48
(d, J = 4.1 Hz, 1H), 7.87 (d, J = 4.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-
nitrothiophen-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-82) ##STR00108## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.02 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 12.1 Hz, 1H), 5.09
(d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.38 (dd, J =
11.5, 2.5 Hz, 1H), 6.54 (td, J = 8.4, 2.5 Hz, 1H), 6.65 (d, J = 8.3
Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.94 (dd, J = 8.3, 2.3 Hz, 1H),
7.02-7.06 (m, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.3 Hz,
1H), 8.04 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-
methylthiothiophen-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-83) ##STR00109## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s,
3H), 2.07 (s, 3H), 2.67 (s, 3H), 3.73 (s, 3H), 4.63 (d, J = 12.1
Hz, 1H), 5.09 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H),
6.37 (dd, J = 11.4, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H),
6.64 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.86 (dd, J =
8.3, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.02-7.06 (m, 1H), 7.20
(d, J = 4.1 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 4.1 Hz,
1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-phenylthiophen-
2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-84) ##STR00110## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s, 3H),
2.08 (s, 3H), 3.75 (s, 3H), 4.64 (d, J = 12.2 Hz, 1H), 5.10 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.38 (dd, J = 11.3, 2.4
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H),
6.82 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 8.2, 2.4 Hz, 1H), 7.03-7.06
(m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H),
7.43-7.46 (m, 1H), 7.49-7.52 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H),
7.73 (d, J = 4.0 Hz, 1H), 7.82-7.84 (m, 1H), 7.83 (d, J = 7.0 Hz,
1H), 8.04 (d, J = 4.0 Hz, 1H)
6-[4-(5-Bromofuran-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(5-
fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-85) ##STR00111## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.73 (s, 3H), 4.62 (d, J = 12.1 Hz, 1H), 5.08 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.37 (dd, J = 11.4, 2.5
Hz, 1H), 6.53 (td, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.80 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.3, 2.3 Hz, 1H), 6.97 (d,
J = 3.7 Hz, 1H), 7.02-7.06 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.22
(d, J = 8.3 Hz, 1H), 7.61 (d, J = 3.7 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-nitrofuran-
2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-86) ##STR00112## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.02 (s, 3H),
2.08 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 12.2 Hz, 1H), 5.09 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J = 11.2, 2.5
Hz, 1H), 6.54 (td, J = 8.4, 2.5 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H),
6.81 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.84
(d, J = 3.9 Hz, 1H), 7.89 (d, J = 3.9 Hz, 1H)
6-[4-(2-Chloro-6-methylpyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-87) ##STR00113## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.17 (s, 3H), 2.02 (s,
3H), 2.08 (s, 3H), 2.60 (s, 3H), 3.73 (s, 3H), 4.62 (d, J = 12.0
Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H),
6.38 (dd, J = 11.4, 2.3 Hz, 1H), 6.54 (td, J = 8.4, 2.3 Hz, 1H),
6.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.94 (dd, J =
8.3, 2.3 Hz, 1H), 7.02- 7.07 (m, 1H), 7.11 (d, J = 2.3 Hz, 1H),
7.26 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 1.0 Hz, 1H), 7.93 (d, J =
1.0 Hz, 1H)
6-[4-(3,5-Dichloropyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-
5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-88) ##STR00114## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.02 (s,
3H), 2.07 (s, 3H), 3.78 (s, 3H), 4.63 (d, J = 12.1 Hz, 1H), 5.09
(d, J = 12.1 Hz, 1H), 5.41 (s, 1H), 6.08 (s, 1H), 6.40 (dd, J =
11.4, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.3
Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.93-6.95 (m, 1H), 6.93 (d, J =
2.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 8.91 (s,
2H) 6-[4-(3-Chloropyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-89) ##STR00115## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.07 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 12.1 Hz, 1H), 5.09
(d, J = 12.1 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J =
11.4, 2.4 Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.3, 2.2 Hz, 1H),
7.03- 7.07 (m, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.3 Hz,
1H), 8.03 (dd, J = 5.0, 1.8 Hz, 1H), 8.10 (dd, J = 1.8, 0.7 Hz,
1H), 8.72 (dd, J = 5.0, 0.7 Hz, 1H)
6-[4-(2-Chloropyridin-4-ylcarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-90) ##STR00116## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.75 (s, 3H), 4.64 (d, J = 12.0 Hz, 1H), 5.10
(d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.5, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.2 Hz, 1H),
7.02- 7.06 (m, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.2 Hz,
1H), 8.06 (d, J = 4.9 Hz, 1H), 8.79 (d, J = 4.9 Hz, 1H), 8.91 (s,
1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(3-fluoropyridin-4-
ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-91) ##STR00117## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.2 Hz, 1H), 5.10
(d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 2.3 Hz, 1H),
7.02- 7.06 (m, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 8.2 Hz,
1H), 8.03-8.05 (m, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.88 (d, J = 2.2
Hz, 1H) 6-(4-Butyryloxy-2-methoxyphenyl)-5-(2-methyl-5-
nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-92) ##STR00118## .sup.1H-NMR (500 MHz, DMSO-D.sub.6) .delta.
0.90 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H), 1.18 (s, 3H), 1.63-1.69 (m,
2H), 2.12 (s, 3H), 2.18 (s, 3H), 2.56 (t, J = 7.2 Hz, 2H), 3.73 (s,
3H), 4.77 (d, J = 12.5 Hz, 1H), 5.30 (d, J = 12.5 Hz, 1H), 5.40 (s,
1H), 6.04 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 8.2, 2.1
Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 7.14
(d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.1 Hz,
1H), 7.63 (dd, J = 8.1, 2.1 Hz, 1H)
6-[2-Methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-methyl-5-
nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-93) ##STR00119## .sup.1H-NMR (500 MHz, DMSO-D.sub.6) .delta.
0.90 (s, 3H), 1.19 (s, 3H), 2.13 (s, 3H), 2.19 (s, 3H), 3.76 (s,
3H), 3.88 (s, 3H), 4.81 (d, J = 12.7 Hz, 1H), 5.34 (d, J = 12.7 Hz,
1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.82 (d,
J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.3 Hz, 1H), 6.99 (d, J = 2.3
Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.24
(d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.9 Hz,
1H), 7.63-7.66 (m, 2H), 7.93 (dd, J = 7.9, 2.0 Hz, 1H)
6-[2-Methoxy-4-(pyridin-3-ylcarbonyloxy)phenyl]-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-94) ##STR00120## .sup.1H-NMR (400 MHz,
DMSO-D.sub.6) .delta. 0.91
(s, 3H), 1.19 (s, 3H), 2.14 (s, 3H), 2.19 (s, 3H), 3.76 (s, 3H),
4.81 (d, J = 12.5 Hz, 1H), 5.33 (d, J = 12.5 Hz, 1H), 5.41 (s, 1H),
6.07 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H),
6.97 (dd, J = 8.3, 2.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.18 (d,
J = 2.2 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.3 Hz,
1H), 7.63-7.68 (m, 2H), 8.48 (dt, J = 8.1, 2.0 Hz, 1H), 8.91 (dd, J
= 4.8, 2.0 Hz, 1H), 9.28 (dd, J = 2.0, 0.7 Hz, 1H)
6-[4-(Furan-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-95) ##STR00121## .sup.1H-NMR (500 MHz,
DMSO-D.sub.6) .delta. 0.91 (s, 3H), 1.19 (s, 3H), 2.13 (s, 3H),
2.19 (s, 3H), 3.75 (s, 3H), 4.80 (d, J = 12.7 Hz, 1H), 5.32 (d, J =
12.7 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.63 (d, J = 8.6 Hz, 1H),
6.81 (dd, J = 3.4, 1.8 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.90 (dd,
J = 8.2, 2.2 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 2.1
Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.57
(dd, J = 3.4, 0.8 Hz, 1H), 7.64 (dd, J = 8.2, 2.1 Hz, 1H), 8.11
(dd, J = 1.8, 0.8 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-
methoxyfuran-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-96) ##STR00122## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.2 Hz, 1H), 5.10
(d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.38 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 8.2
Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 2.3 Hz, 1H),
7.02-7.06 (m, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 8.2 Hz,
1H), 8.03-8.05 (m, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.88 (d, J = 2.2
Hz, 1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(5-
methylpyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-97) ##STR00123## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.16 (s, 3H), 2.03 (s,
3H), 2.08 (s, 3H), 2.43 (s, 3H), 3.74 (s, 3H), 4.64 (d, J = 12.5
Hz, 1H), 5.10 (d, J = 12.5 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H),
6.36 (dd, J = 11.5, 2.4 Hz, 1H), 6.54 (td, J = 8.3, 2.4 Hz, 1H),
6.65 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.92 (dd, J =
8.2, 2.2 Hz, 1H), 7.03-7.07 (m, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.25
(d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 8.75 (s, 1H), 9.08 (s, 1H)
6-[4-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-98) ##STR00124## .sup.1H-NMR (400 MHz,
DMSO-d.sub.3) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.72 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 12.0 Hz, 1H), 5.28 (d, J =
12.0 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.79 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.2 , 2.2 Hz, 1H), 7.01 (d,
J = 2.2 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.2 Hz,
1H), 7.34 (d, J = 2.7 Hz, 1H), 7.54-7.58 (m, 1H), 7.67-7.69 (m,
2H), 7.82 (dd, J = 9.0, 2.7 Hz, 1H), 8.09 (ddd, J = 7.7, 1.2, 0.7
Hz, 1H) 5-(2-Methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-
(pyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-99) ##STR00125## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 3.70 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 11.9 Hz, 1H), 5.28
(d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.64 (d, J = 8.2
Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.3, 2.3 Hz, 1H),
7.05 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 7.21 (d, J =
8.3 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.66 (ddd, J = 8.1, 4.9, 1.0
Hz, 1H), 7.82 (dd, J = 9.1, 2.7 Hz, 1H), 8.46 (dt, J = 8.1, 1.9 Hz,
1H), 8.90 (dd, J = 4.9, 1.9 Hz, 1H), 9.25 (dd, J = 1.9, 1.0 Hz, 1H)
5-(2-Methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-
(pyridin-4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-100) ##STR00126## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 3.70 (s, 3H), 3.83 (s, 3H), 4.68 (d, J = 11.9 Hz, 1H), 5.27
(d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.64 (d, J = 8.1
Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.85 (dd, J = 8.2, 2.4 Hz, 1H),
7.05 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 7.22 (d, J =
8.2 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.82 (dd, J = 9.1, 2.7 Hz,
1H), 8.00 (d, J = 6.0 Hz, 2H), 8.89 (d, J = 6.0 Hz, 2H)
6-[2-Methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-
5-(2-methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-101) ##STR00127## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 2.78 (s, 3H), 3.71 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 12.3
Hz, 1H), 5.28 (d, J = 12.3 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H),
6.64 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.84 (dd, J =
8.3, 2.2 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.0 Hz,
1H), 7.21 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.47 (dd,
J = 8.1, 4.9 Hz, 1H), 7.82 (dd, J = 9.0, 2.8 Hz, 1H), 8.42 (dd, J =
8.1, 1.8 Hz, 1H), 8.71 (dd, J = 4.9, 1.8 Hz, 1H)
6-[2-Methoxy-4-(2-methoxybenzoyloxy)phenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-102) ##STR00128## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.71 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.69 (d, J = 12.2 Hz,
1H), 5.28 (d, J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.02 (s, 1H), 6.63
(d, J = 8.2 Hz, 1H), 6.77 (dd, J = 7.9, 2.2 Hz, 1H), 6.78 (d, J =
8.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H),
7.10 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.23 (d, J =
8.1 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.64 (ddd, J = 8.1, 7.3, 1.7
Hz, 1H), 7.82 (dd, J = 9.1, 2.6 Hz, 1H), 7.90 (dd, J = 7.3, 1.7 Hz,
1H) 6-[4-(Furan-2-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-103) ##STR00129## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.69 (s, 3H), 3.82 (s, 3H), 4.67 (d, J = 11.9 Hz, 1H), 5.27 (d, J =
11.9 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.79 (dd, J = 8.2, 2.2 Hz, 1H), 6.80 (dd,
J = 3.5, 1.8 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.2
Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 7.55
(dd, J = 3.5, 0.9 Hz, 1H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 8.10
(dd, J = 1.8, 0.9 Hz, 1H)
6-(4-Isopropylcarbonyloxy-2-methoxyphenyl)-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-104) ##STR00130## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.03 (s, 3H), 1.18 (s, 3H), 1.23 (d, J = 7.0
Hz, 6H), 2.14 (s, 3H), 2.76-2.82 (m, 1H), 3.68 (s, 3H), 3.81 (s,
3H), 4.65 (d, J = 12.1 Hz, 1H), 5.25 (d, J = 12.1 Hz, 1H), 5.39 (s,
1H), 6.01 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.63 (dd, J = 7.9, 2.1
Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 7.08
(d, J = 9.2 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 2.7 Hz,
1H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H)
6-[2-Methoxy-4-(3-methoxycarbonylbenzoyloxy)phenyl]-
5-(2-methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-105) ##STR00131## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 3.71 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 4.69 (d, J = 12.0
Hz, 1H), 5.28 (d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H),
6.64 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.85 (dd, J =
8.2, 2.2 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.2 Hz,
1H), 7.22 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.79 (t, J
= 8.1 Hz, 1H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 8.31 (d, J = 8.1 Hz,
1H), 8.38 (d, J = 8.1 Hz, 8.64 (s, 1H)
6-[4-(3-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-106) ##STR00132## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.70 (s, 3H), 3.83 (s, 3H), 4.68 (d, J = 11.9 Hz, 1H), 5.28 (d, J =
11.9 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.79 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H), 7.03 (d,
J = 2.2 Hz, 1H), 7.09 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 8.2 Hz,
1H), 7.34 (d, J = 2.6 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.82 (dd,
J = 9.3, 2.6 Hz, 1H), 7.83-7.85 (m, 1H), 8.06-8.11 (m, 2H)
6-[4-(4-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-5-
nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-107) ##STR00133## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H), 3.70 (s, 3H), 3.83 (s,
3H), 4.69 (d, J = 11.8 Hz, 1H), 5.28 (d, J = 11.8 Hz, 1H), 5.40 (s,
1H), 6.03 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.1 Hz,
1H), 6.82 (dd, J = 7.9, 2.1 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 7.09
(d, J = 9.1 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 2.7 Hz,
1H), 7.69 (d, J = 8.6 Hz, 2H), 7.82 (dd, J = 9.1, 2.7 Hz, 1H), 8.12
(d, J = 8.6 Hz, 2H)
6-(4-Butyryloxy-2-methoxyphenyl)-5-(2-methoxy-5-
nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-108) ##STR00134## .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta.
0.97 (t, J = 7.5 Hz, 3H), 1.03 (s, 3H), 1.18 (s, 3H), 1.65 (qt, J =
7.5, 7.4 Hz, 2H), 2.14 (s, 3H), 2.53 (t, J = 7.4 Hz, 2H), 3.67 (s,
3H), 3.81 (s, 3H), 4.65 (d, J = 11.9 Hz, 1H), 5.25 (d, J = 11.9 Hz,
1H), 5.39 (s, 1H), 6.01 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.64
(dd, J = 8.3, 2.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.79 (d, J =
2.4 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H),
7.31 (d, 2.7 Hz, 1H), 7.81 (dd, J = 9.1, 2.7 Hz, 1H)
6-(4-Benzoyloxy-2-methoxyphenyl)-5-(2-methoxy-5-
nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 1-109) ##STR00135## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
1.04 (s, 3H), 1.27 (s, 3H), 2.28 (s, 3H), 3.77 (s, 3H), 3.84 (s,
4H), 4.88 (d, J = 12.3 Hz, 1H), 5.40 (d, J = 12.3 Hz, 1H), 5.47 (s,
1H), 6.57 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.81 (d, J
= 2.2 Hz, 1H), 6.84 (d, J = 8.1, 2.2 Hz, 1H), 6.90 (d, J = 8.1 Hz,
1H), 7.32 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.52 (t, J
= 7.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.7 Hz,
1H), 8.21 (d, J = 7.4 Hz, 2H)
6-[2-Methoxy-4-(2-methylbenzoyloxy)phenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-110) ##STR00136## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.02 (s, 3H), 1.27 (s, 3H), 2.28 (s, 3H), 2.69 (s, 3H),
3.78 (s, 3H), 3.85 (s, 4H), 4.88 (d, J = 12.5 Hz, 1H), 5.40 (d, J =
12.5 Hz, 1H), 5.46 (s, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.78 (d, J =
8.9 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.1, 2.1 Hz,
1H), 6.90 (d, J = 8.1 Hz, 1H), 7.31-7.35 (m, 3H), 7.31 (d, J = 2.7
Hz, 1H), 7.47-7.51 (m, 1H), 7.78 (dd, J = 8.9, 2.7 Hz, 1H), 8.17
(dd, J = 8.5, 1.5 Hz, 1H)
6-[4-(2-Chlorobenzoyloxy)-2-methoxyphenyl]-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl,1-2-dihydroquinoline
(Compound No. 1-111) ##STR00137## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.91 (s, 3H), 1.19 (s, 3H), 2.14 (s, 3H),
2.19 (s, 3H), 3.77 (s, 3H), 4.81 (d, J = 12.9 Hz, 1H), 5.34 (d, J =
12.9 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.64 (d, J = 8.3 Hz, 1H),
6.83 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.2, 2.2 Hz, 1H), 7.08 (d,
J = 2.2 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.2 Hz,
1H), 7.35 (d, J = 8.2 Hz, 1H), 7.55-7.59 (m, 1H), 7.64 (d, J = 8.2,
2.2 Hz, 1H), 7.68-7.69 (m, 2H), 8.11 (d, J = 7.6 Hz, 1H)
6-[2-Methoxy-4-(3-methylbenzoyloxy)phenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-112) ##STR00138## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
2.42 (s, 3H), 3.70 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 12.1 Hz,
1H), 5.28 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.64
(d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 7.9,
2.2 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H),
7.20 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.49 (t, J =
7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.82 (dd, J = 9.1, 2.5 Hz,
1H), 7.92 (d, J = 7.7 Hz, 1H), 7.95 (s, 1H)
6-[2-Methoxy-4-(4-methylbenzoyloxy)phenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-113) ##STR00139## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
2.43 (s, 3H), 3.70 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 11.9 Hz,
1H), 5.28 (d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.63
(d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.0,
2.2 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H),
7.19 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.42 (d, J =
8.2 Hz, 2H), 7.82 (dd, J = 9.1, 2.7 Hz, 1H), 8.01 (d, J = 8.2 Hz,
2H) 5-(2-Methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-
(thiophen-2-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-114) ##STR00140## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 3.70 (s, 3H), 3.83 (s, 3H), 4.68 (d, J = 12.1 Hz, 1H), 5.27
(d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.63 (d, J = 8.3
Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 8.2, 2.2 Hz, 1H),
6.98 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 7.19 (d, J =
8.2 Hz, 1H), 7.31 (dd, J = 5.0, 3.8 Hz, 1H), 7.34 (d, J = 2.7 Hz,
1H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 8.01 (dd, J = 3.8, 1.2 Hz,
1H), 8.10 (dd, J = 5.0, 1.2 Hz, 1H)
5-(2-Methoxy-5-nitrophenoxymethyl)-6-[2-methoxy-4-
(thiophen-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 1-115) ##STR00141## .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s,
3H), 3.69 (s, 3H), 3.83 (s, 3H), 4.68 (d, J = 11.9 Hz, 1H), 5.27
(d, J = 11.9 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.63 (d, J = 8.2
Hz, 1H), 6.78 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 2.1 Hz, 1H), 7.09
(d, J = 9.1 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.7 Hz,
1H), 7.60 (dd, J = 5.1, 1.2 Hz, 1H), 7.75 (dd, J = 5.1, 3.1 Hz,
1H), 7.82 (dd, J = 9.1, 2.7 Hz, 1H), 8.58 (dd, J = 3.1, 1.2 Hz, 1H)
6-[4-(2-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-116) ##STR00142## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.71 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 11.9 Hz, 1H), 5.28 (d, J =
11.9 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.79 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.2, 2.3 Hz, 1H), 7.01 (d,
J = 2.3 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 8.2 Hz,
1H), 7.34 (d, J = 2.7 Hz, 1H), 7.40- 7.46 (m, 2H), 7.75-7.81 (m,
1H), 7.82 (dd, J = 9.0, 2.7 Hz, 1H), 8.09 (t, J = 7.7 Hz, 1H)
6-[4-(4-Fluorobenzoyloxy)-2-methoxyphenyl]-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-117) ##STR00143## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.70 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 11.9 Hz, 1H), 5.28 (d, J =
11.9 Hz, 1H), 5.40 (s, 1H), 6.03 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.79 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 8.1, 2.3 Hz, 1H), 7.00 (d,
J = 2.3 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 7.20 (d, J = 8.1 Hz,
1H), 7.33 (d, J = 2.7 Hz, 1H), 7.45 (t, J = 9.1 Hz, 2H), 7.82 (dd,
J = 9.1, 2.7 Hz, 1H), 8.19 (dd, J = 9.1, 5.5 Hz, 2H)
6-[2-Methoxy-4-(2-nitrobenzoyloxy)phenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-118) ##STR00144## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.71 (s, 3H), 3.82 (s, 3H), 4.69 (d, J = 12.1 Hz, 1H), 5.27 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.63 (d, J = 8.3 Hz, 1H),
6.78 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 8.2, 2.2 Hz, 1H), 6.97 (d,
J = 2.2 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 7.23 (d, J = 8.2 Hz,
1H), 7.33 (d, J = 2.7 Hz, 1H), 7.81 (dd, J = 9.0, 2.7 Hz, 1H), 7.91
(td, J = 7.7, 1.6 Hz, 1H), 7.96 (td, J = 7.7, 1.3 Hz, 1H), 8.10
(dd, J = 7.7, 1.6 Hz, 1H), 8.19 (dd, J = 7.7, 1.3 Hz, 1H)
6-[2-Methoxy-4-(4-methoxybenzoyloxy)phenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-119) ##STR00145## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.19 (s, 3H), 2.15 (s, 3H),
3.70 (s, 3H), 3.83 (s, 3H), 3.88 (s, 3H), 4.69 (d, J = 11.8 Hz,
1H), 5.28 (d, J = 11.8 Hz, 1H), 5.40 (s, 1H), 6.02 (s, 1H), 6.63
(d, J = 8.2 Hz, 1H), 6.78 (dd, J = 8.0, 2.2 Hz, 1H), 6.78 (d, J =
8.2 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H),
7.13 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.33 (d, J =
2.5 Hz, 1H), 7.82 (dd, J = 9.1, 2.5 Hz, 1H), 8.07 (d, J = 8.9 Hz,
2H) 6-[2-Methoxy-4-(thiophen-3-ylcarbonyloxy)phenyl]-5-(2-
methyl-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-120) ##STR00146## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.91 (s, 3H), 1.19 (s, 3H), 2.13 (s, 3H),
2.19 (s, 3H), 3.75 (s, 3H), 4.80 (d, J = 12.7 Hz, 1H), 5.33 (d, J =
12.7 Hz, 1H), 5.41 (s, 1H), 6.05 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.82 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 8.3, 2.2 Hz, 1H), 7.02 (d,
J = 2.2 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 8.3 Hz,
1H), 7.34 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 5.1, 1.3 Hz, 1H), 7.64
(dd, J = 8.1, 2.1 Hz, 1H), 7.75 (dd, J = 5.1, 2.9 Hz, 1H), 8.61
(dd, J = 2.9, 1.3 Hz, 1H)
6-[4-(Furan-3-ylcarbonyloxy)-2-methoxyphenyl]-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-121) ##STR00147## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.91 (s, 3H), 1.18 (s, 3H), 2.13 (s, 3H),
2.19 (s, 3H), 3.74 (s, 3H), 4.79 (d, J = 12.2 Hz, 1H), 5.32 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.63 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.1, 2.4 Hz, 1H), 6.94 (dd,
J = 1.7, 0.7 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.3
Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.64
(dd, J = 8.2, 2.3 Hz, 1H), 7.92 (t, J = 1.7 Hz, 1H), 8.64 (dd, J =
1.7, 0.7 Hz, 1H)
6-[2-Methoxy-4-(2-methylpyridin-3-ylcarbonyloxy)phenyl]-5-(2-
methyl-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2- dihydroquinoline
(Compound No. 1-122) ##STR00148## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.91 (s, 3H), 1.19 (s, 3H), 2.14 (s, 3H),
2.19 (s, 3H), 2.80 (s, 3H), 3.76 (s, 3H), 4.81 (d, J = 12.7 Hz,
1H), 5.34 (d, J = 12.7 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.64
(d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.1,
2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H),
7.34 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 8.0, 4.9 Hz, 1H), 7.64 (dd,
J = 8.1, 2.1 Hz, 1H), 8.45 (dd, J = 8.0, 1.7 Hz, 1H), 8.72 (dd, J =
4.9, 1.7 Hz, 1H)
6-[2-Methoxy-4-(3-methylfuran-2-ylcarbonyloxy)phenyl]-5-
(2-methyl-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-123) ##STR00149## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.90 (s, 3H), 1.19 (s, 3H), 2.13 (s, 3H),
2.19 (s, 3H), 2.38 (s, 3H), 3.75 (s, 3H), 4.81 (d, J = 12.5 Hz,
1H), 5.33 (d, J = 12.5 Hz, 1H), 5.40 (s, 1H), 6.04 (s, 1H), 6.63
(d, J = 8.1 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 6.81 (d, J = 8.1 Hz,
1H), 6.89 (dd, J = 8.2, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.17
(d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz,
1H), 7.64 (dd, J = 8.2, 2.3 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H)
6-[2-Methoxy-4-(pyridin-4-ylcarbonyloxy)phenyl]-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 1-124) ##STR00150## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.91 (s, 3H), 1.19 (s, 3H), 2.13 (s, 3H),
2.19 (s, 3H), 3.75 (s, 3H), 4.81 (d, J = 12.7 Hz, 1H), 5.33 (d, J =
12.7 Hz, 1H), 5.41 (s, 1H), 6.06 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.83 (d, J = 8.2 Hz, 1H), 6.97 (dd, J = 8.2, 2.1 Hz, 1H), 7.11 (d,
J = 2.1 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.2 Hz,
1H), 7.34 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.2, 2.2 Hz, 1H), 8.02
(d, J = 6.1 Hz, 2H), 8.90 (d, J = 6.1 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-
(2-methoxypyridin-3-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-
1,2-dihydroquinoline (Compound No. 1-125) ##STR00151## .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.03
(s, 3H), 2.08 (s, 3H), 3.74 (s, 3H), 3.98 (s, 3H), 4.64 (d, J =
12.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.04 (s,
1H), 6.37 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz,
1H), 6.65 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.86 (dd,
J = 8.1, 2.3 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 7.02-7.06 (m, 1H),
7.20 (dd, J = 7.6, 4.9 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 8.41 (dd,
J = 7.6, 2.0 Hz, 1H), 8.48 (dd, J = 4.9, 2.0 Hz, 1H)
Example 2
6-(5-Acetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-tri-
methyl-1,2-dihydroquinoline (Compound No. 2)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(5-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 62.5 mg,
0.14 mmol) and triethylamine (154 .mu.L, 1.11 mmol) were dissolved
in anhydrous methylene dichloride (1 mL), acetic anhydride (52
.mu.L, 0.55 mmol) was added thereto, and then the mixture was
stirred at room temperature for 1.5 hours. Chloroform (10 mL) was
added to the reaction mixture, the mixture was washed with water
(10 mL) and saturated brine (300 mL) successively, dried over
anhydrous magnesium sulfate, and then the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate) to give the titled compound
(56.6 mg) as a colorless amorphous product. (Yield 83%)
TABLE-US-00016 ##STR00152## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.15 (s, 3H), 1.22 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H),
2.25 (s, 3H), 3.74 (s, 3H), 4.01 (br s, 1H), 4.75 (d, J = 12.0 Hz,
1H), 5.10 (d, J = 12.0 Hz, 1H), 5.46 (s, 1H), 6.22 (dd, J = 11.2,
2.4 Hz, 1H), 6.43 (td, J = 8.3, 2.4 Hz, 1H), 6.58 (d, J = 8.1 Hz,
1H), 6.90-6.96 (m, 3H), 6.99 (d, J = 2.9 Hz, 1H), 7.03 (dd, J =
8.8, 2.9 Hz, 1H)
Example 3
6-(4-Aminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,-
4-trimethyl-1,2-dihydroquinoline monohydrochloride (Compound No.
3-1)
6-(4-t-Butoxycarbonylaminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylph-
enoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference
Compound No. 4-1, 20.1 mg, 0.034 mmol) was dissolved in 1,4-dioxane
(0.5 mL), 4N hydrogen chloride/1,4-dioxane solution (34 .mu.L) was
added thereto, and then the mixture was stirred at room temperature
overnight. The reaction mixture was concentrated under reduced
pressure to give the titled compound (17.5 mg) as a colorless
solid. (Yield 98%)
TABLE-US-00017 ##STR00153## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.09 (s, 3H), 1.18 (s, 3H), 2.01 (s, 3H), 2.09 (s, 3H),
3.73 (s, 3H), 4.09-4.10 (m, 2H), 4.61 (d, J = 12.1 Hz, 1H), 5.08
(d, J = 12.1 Hz, 1H), 5.47 (s, 1H), 6.35 (dd, J = 11.5, 2.4 Hz,
1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.75- 6.87 (m, 1H), 6.80 (dd,
J = 8.3, 2.2 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 2.2
Hz, 1H), 7.02-7.06 (m, 1H), 7.25 (d, J = 8.3 Hz, 1H), 8.49 (br s,
3H)
Using Compound No. 1-51, the following Compound No. 3-2 was
obtained by a method similar to that of Compound No. 3-1.
TABLE-US-00018 5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) methyl)-6-[2-methoxy-4-(piper- .delta. 1.12 (s, 3H),
1.23 (s, 3H), idin-4-ylcarbonyloxy)phenyl]- 1.87-1.95 (m, 2H), 2.01
2,2,4-trimethyl-1,2-dihydro- (s, 3H), 2.10 (s, 3H), 2.10- quinoline
monohydrochloride 2.17 (m, 2H), 2.96-3.01 (m, 3H), (Compound No.
3-2) 3.29-3.32 (m, 2H), 3.74 ##STR00154## (s, 3H), 4.66 (d, J =
12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.57 (s, 1H), 6.34 (dd, J
= 11.5, 2.4 Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.79 (dd, J =
8.2, 2.2 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.93- 7.00 (m, 2H),
6.96 (br s, 1H), 7.03-7.06 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H), 8.88
(br s, 1H), 9.08 (br s, 1H)
Example 4
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methylsulfonyloxyphenyl)-
-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 4-1)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 61.0 mg,
0.141 mmol) was dissolved in methylene dichloride (2 mL),
methanesulfonyl chloride (26 .mu.L, 0.34 mmol) and triethylamine
(92 .mu.L, 0.66 mmol) were added thereto, and then the mixture was
stirred at room temperature overnight. The reaction mixture was
purified by silica gel column chromatography (hexane-ethyl acetate)
to give the titled compound (58.0 mg) as a pale pink solid. (Yield
82%)
TABLE-US-00019 ##STR00155## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.07 (s, 3H), 1.15 (s, 3H), 2.00 (s, 3H), 2.07 (s, 3H),
3.37 (s, 3H), 3.75 (s, 3H), 4.60 (d, J = 12.2 Hz, 1H), 5.06 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.36 (dd, J = 11.3, 2.5
Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.3 Hz, 1H), 7.02-7.05
(m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H)
Using any compounds among Reference Compounds No. 3-1, 3-3 and 3-4,
the following Compounds (No. 4-2.about.4-30) were obtained by a
method similar to that of Compound No. 4-1.
TABLE-US-00020 5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) methyl)-6-(2-methoxy-4-phen- .delta. 1.07 (s, 3H),
1.14 (s, 3H), ylsulfonyloxyphenyl)-2,2,4- 1.98 (s, 3H), 2.04 (s,
3H), trimethyl-1,2-dihydroquino- 3.55 (s, 3H), 4.47 (d, J = 11.9
line (Compound No. 4-2) Hz, 1H), 4.97 (d, J = 11.9 Hz, ##STR00156##
1H), 5.39 (s, 1H), 6.06 (s, 1H), 6.35 (dd, J = 11.3, 2.5 Hz, 1H),
6.57 (td, J = 8.4, 2.5 Hz, 1H), 6.59 (dd, J = 8.9, 2.4 Hz, 1H),
6.59 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.71 (d, J =
8.2 Hz, 1H), 7.05-7.08 (m, 1H), 7.12 (d, J = 8.9 Hz, 1H), 7.56-7.59
(m, 2H), 7.76-7.81 (m, 3H) 6-[4-(2-Chlorophenylsulfonyl-
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) oxy)-2-methoxyphenyl]-5-(5-
.delta. 1.06 (s, 3H), 1.14 (s, 3H), fluoro-2-methylphenoxymeth-
1.96 (s, 3H), 2.02 (s, 3H), yl)-2,2,4-trimethyl-1,2-di- 3.60 (s,
3H), 4.45 (d, J = 12.1 hydroquinoline (Compound No. Hz, 1H), 4.96
(d, J = 12.1 Hz, 4-3) 1H), 5.39 (s, 1H), 6.06 (s, ##STR00157## 1H),
6.30 (dd, J = 11.3, 2.4 Hz, 1H), 6.56 (td, J = 8.4, 2.4 Hz, 1H),
6.60 (d, J = 8.2 Hz, 1H), 6.61-6.63 (m, 1H), 6.70 (d, J = 8.2 Hz,
1H), 6.72 (d, J = 2.4 Hz, 1H), 7.03-7.06 (m, 1H), 7.13 (d, J = 8.2
Hz, 1H), 7.47 (td, J = 7.9, 1.2 Hz, 1H), 7.77 (td, J = 7.9, 1.7 Hz,
1H), 7.84 (dd, J = 7.9, 1.2 Hz, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H)
6-[4-(3-Chlorophenylsulfonyl- .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
oxy)-2-methoxyphenyl]-5-(5- .delta. 1.07 (s, 3H), 1.14 (s, 3H),
fluoro-2-methylphenoxymeth- 1.98 (s, 3H), 2.04 (s, 3H),
yl)-2,2,4-trimethyl-1,2-di- 3.60 (s, 3H), 4.50 (d, J = 12.0
hydroquinoline (Compound No. Hz, 1H), 4.99 (d, J = 12.0 Hz, 4-4)
1H), 5.39 (s, 1H), 6.07 (s, ##STR00158## 1H), 6.32 (dd, J = 11.2,
2.5 Hz, 1H), 6.55 (td, J = 8.5, 2.5 Hz, 1H), 6.61 (d, J = 8.1 Hz,
1H), 6.65 (dd, J = 8.2, 2.3 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.72
(d, J = 8.1 Hz, 1H), 7.03-7.06 (m, 1H), 7.16 (d, J = 8.2 Hz, 1H),
7.61 (t, J = 8.0 Hz, 1H), 7.77 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H),
7.88 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 7.91 (t, J = 1.8 Hz, 1H)
6-[4-(4-Chlorophenylsulfonyl- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
oxy)-2-methoxyphenyl]-5-(5- .delta. 1.07 (s, 3H), 1.14 (s, 3H),
fluoro-2-methylphenoxymeth- 1.99 (s, 3H), 2.04 (s, 3H),
yl)-2,2,4-trimethyl-1,2-di- 3.59 (s, 3H), 4.49 (d, J = 12.1
hydroquinoline (Compound No. Hz, 1H), 4.99 (d, J = 12.1 Hz, 4-5)
1H), 5.40 (s, 1H), 6.07 (s, ##STR00159## 1H), 6.37 (dd, J = 11.3,
2.5 Hz, 1H), 6.56 (td, J = 8.5, 2.5 Hz, 1H), 6.59 (dd, J = 8.4, 2.1
Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.72
(d, J = 8.2 Hz, 1H), 7.04-7.07 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H),
7.63 (d, J = 8.9 Hz, 2H), 7.81 (d, J = 8.9 Hz, 2H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methyl)-6-[2-methoxy-4-(3- .delta. 1.06 (s, 3H), 1.14 (s, 3H),
methoxyphenylsulfonyloxy) 1.98 (s, 3H), 2.04 (s, 3H),
phenyl]-2,2,4-trimethyl-1,2-di- 3.58 (s, 3H), 3.79 (s, 3H), 4.50
hydroquinoline (Compound (d, J = 12.1 Hz, 1H), 4.99 No. 4-6) (d, J
= 12.1 Hz, 1H), 5.39 (s, ##STR00160## 1H), 6.06 (s, 1H), 6.31 (dd,
J = 11.6, 2.4 Hz, 1H), 6.55 (td, J = 8.4, 2.4 Hz, 1H), 6.61 (d, J =
8.2 Hz, 1H), 6.63 (dd, J = 8.3, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz,
1H), 6.72 (d, J = 8.2 Hz, 1H), 7.03-7.06 (m, 1H), 7.14 (d, J = 8.3
Hz, 1H), 7.32-7.35 (m, 3H), 7.47 (t, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methyl)-6-[2-methoxy-4-(4- .delta. 1.07 (s, 3H), 1.14 (s, 3H),
methoxyphenylsulfonyloxy) 1.99 (s, 3H), 2.05 (s, 3H),
phenyl]-2,2,4-trimethyl-1,2-di- 3.58 (s, 3H), 3.82 (s, 3H), 4.49
hydroquinoline (Compound (d, J = 12.1 Hz, 1H), 4.99 No. 4-7) (d, J
= 12.1 Hz, 1H), 5.39 (s, ##STR00161## 1H), 6.06 (s, 1H), 6.35 (dd,
J = 11.6, 2.5 Hz, 1H), 6.55 (td, J = 8.4, 2.5 Hz, 1H), 6.57 (dd, J
= 8.2, 2.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 8.1 Hz,
1H), 6.72 (d, J = 8.1 Hz, 1H), 7.04-7.07 (m, 1H), 7.05 (d, J = 9.2
Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 9.2 Hz, 2H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methyl)-6-(2-methoxy-4-tri- .delta. 1.09 (s, 3H), 1.16 (s, 3H),
fluoromethylsulfonyloxyphenyl)- 1.99 (s, 3H), 2.06 (s, 3H),
2,2,4-trimethyl-1,2-dihydro- 3.77 (s, 3H), 4.55 (d, J = 11.9
quinoline (Compound No. 4-8) Hz, 1H), 5.03 (d, J = 11.9 Hz,
##STR00162## 1H), 5.41 (s, 1H), 6.11 (s, 1H), 6.36 (dd, J = 11.6,
2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz,
1H), 6.78 (d, J = 8.2 Hz, 1H), 7.02-7.05 (m, 1H), 7.03 (dd, J =
8.4, 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.4. Hz,
1H) 6-(4-Benzylsulfonyloxy-2- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methoxyphenyl)-5-(5-fluoro-2- .delta. 1.06 (s, 3H), 1.15 (s, 3H),
methylphenoxymethyl)-2,2,4- 2.01 (s, 3H), 2.06 (s, 3H),
trimethyl-1,2-dihydroquino- 3.70 (s, 3H), 4.58 (d, J = 12.1 line
(Compound No. 4-9) Hz, 1H), 4.97 (s, 2H), 5.05 ##STR00163## (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.37 (dd, J = 11.3, 2.4
Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.76 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.83 (dd, J =
8.2, 2.3 Hz, 1H), 7.02-7.05 (m, 1H), 7.21 (d, J = 8.2 Hz, 1H),
7.41-7.44 (m, 3H), 7.47-7.49 (m, 2H) 5-(5-Fluoro-2-methylphenoxy-
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) methyl)-6-[4-(furan-2-yl-
.delta. 1.08 (s, 3H), 1.15 (s, 3H), sulfonyloxy)-2-methoxyphenyl]-
1.98 (s, 3H), 2.04 (s, 3H), 2,2,4-trimethyl-1,2-dihydro- 3.63 (s,
3H), 4.49 (d, J = 11.8 quinoline (Compound No. 4-10) Hz, 1H), 4.99
(d, J = 11.8 Hz, ##STR00164## 1H), 5.40 (s, 1H), 6.08 (s, 1H), 6.36
(dd, J = 11.5, 2.4 Hz, 1H), 6.56 (td, J = 8.4, 2.4 Hz, 1H), 6.60
(dd, J = 8.1, 2.6 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.65 (d, J =
2.6 Hz, 1H), 6.70 (dd, J = 3.7, 1.8 Hz, 1H), 6.73 (d, J = 8.3 Hz,
1H), 7.04-7.08 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.24 (dd, J =
3.7, 0.9 Hz, 1H), 8.19 (dd, J = 1.8, 0.9 Hz, 1H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
methyl)-6-(2-methoxy-4-prop- .delta. 1.01 (t, J = 7.5 Hz, 3H),
ylsulfonyloxyphenyl)-2,2,4- 1.07 (s, 3H), 1.15 (s, 3H), 1.83
trimethyl-1,2-dihydroquino- (sextet, J = 7.5 Hz, 2H), line
(Compound No. 4-11) 2.00 (s, 3H), 2.06 (s, 3H), 3.48 ##STR00165##
(t, J = 7.5 Hz, 2H), 3.75 (s, 3H), 4.58 (d, J = 12.0 Hz, 1H), 5.05
(d, J = 12.0 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.36 (dd, J =
11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.1
Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.91 (dd, J = 8.3, 2.4 Hz, 1H),
6.98 (d, J = 2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.23 (d, J = 8.3 Hz,
1H) 6-(4-Ethylsulfonyloxy-2-meth- .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) oxyphenyl)-5-(5-fluoro-2- .delta. 1.07 (s, 3H), 1.15
(s, 3H), methylphenoxymethyl)-2,2,4- 1.35 (t, J = 7.3 Hz, 3H), 2.00
trimethyl-1,2-dihydroquinoline (s, 3H), 2.06 (s, 3H), 3.50
(Compound No. 4-12) (q, J = 7.3 Hz, 2H), 3.75 (s, ##STR00166## 3H),
4.58 (d, J = 12.0 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 5.40 (s, 1H),
6.07 (s, 1H), 6.36 (dd, J = 11.5, 2.5 Hz, 1H), 6.53 (td, J = 8.4,
2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H),
6.91 (dd, J = 8.3, 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 7.01-7.05
(m, 1H), 7.23 (d, J = 8.3 Hz, 1H) 5-(5-Fluoro-2-methylphenoxy-
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) methyl)-6-(4-isopropylsulfon-
.delta. 1.07 (s, 3H), 1.15 (s, 3H), yloxy-2-methoxyphenyl)-2,2,4-
1.42 (d, J = 6.7 Hz, 6H), 2.01 trimethyl-1,2-dihydro- (s, 3H), 2.06
(s, 3H), 3.70 quinoline (Compound No. 4-13) (septet, J = 6.7 Hz,
1H), 3.75 ##STR00167## (s, 3H), 4.58 (d, J = 12.2 Hz, 1H), 5.05 (d,
J = 12.2 Hz, 1H), 5.40 (s, 1H), 6.07 (s, 1H), 6.37 (dd, J = 11.3,
2.5 Hz, 1H), 6.53 (td, J = 8.5, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz,
1H), 6.77 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 8.2, 2.4 Hz, 1H), 6.95
(d, J = 2.4 Hz, 1H), 7.02-7.05 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H)
6-(4-Butylsulfonyloxy-2-meth- .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
oxyphenyl)-5-(5-fluoro-2- .delta. 0.89 (t, J = 7.6 Hz, 3H),
methylphenoxymethyl)-2,2,4- 1.07 (s, 3H), 1.15 (s, 3H), 1.42
trimethyl-1,2-dihydroquinoline (sextet, J = 7.6 Hz, 2H), (Compound
No. 4-14) 1.78 (quintet, J = 7.6 Hz, 2H), ##STR00168## 2.00 (s,
3H), 2.06 (s, 3H), 3.49 (t, J = 7.6 Hz, 2H), 3.75 (s, 3H), 4.58 (d,
J = 12.1 Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.07 (s,
1H), 6.36 (dd, J = 11.5, 2.4 Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz,
1H), 6.64 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.92 (dd,
J = 8.3, 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 7.01-7.05 (m, 1H),
7.23 (d, J = 8.3 Hz, 1H) 5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) methyl)-6-[2-methoxy-4-(2- .delta. 1.06 (s,
3H), 1.14 (s, 3H), methylphenylsulfonyloxy)phen- 1.97 (s, 3H), 2.03
(s, 3H), yl]-2,2,4-trimethyl-1,2-di- 2.64 (s, 3H), 3.55 (s, 3H),
4.45 hydroquinoline (Compound No. (d, J = 11.7 Hz, 1H), 4.96 4-15)
(d, J = 11.7 Hz, 1H), 5.39 (s, ##STR00169## 1H), 6.06 (s, 1H), 6.32
(dd, J = 11.4, 2.5 Hz, 1H), 6.56 (td, J = 8.2, 2.5 Hz, 1H), 6.56-
6.58 (m, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H),
6.70 (d, J = 8.3 Hz, 1H), 7.04-7.07 (m, 1H), 7.11 (d, J = 8.1 Hz,
1H), 7.30-7.34 (m, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.66 (td, J =
7.7, 1.2 Hz, 1H), 7.71 (dd, J = 7.7, 1.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methyl)-6-[4-(2-fluorophenyl- .delta. 1.07 (s, 3H), 1.14 (s, 3H),
sulfonyloxy)-2-methoxyphen- 1.97 (s, 3H), 2.03 (s, 3H),
yl]-2,2,4-trimethyl-1,2-di- 3.60 (s, 3H), 4.46 (d, J = 12.1
hydroquinoline (Compound No. Hz, 1H), 4.96 (d, J = 12.1 Hz, 4-16)
1H), 5.39 (s, 1H), 6.06 (s, ##STR00170## 1H), 6.31 (dd, J = 11.3,
2.5 Hz, 1H), 6.56 (td, J = 8.4, 2.5 Hz, 1H), 6.59 (d, J = 8.2 Hz,
1H), 6.63 (dd, J = 8.3, 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.71
(d, J = 8.2 Hz, 1H), 7.04-7.07 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H),
7.34 (td, J = 7.7, 0.9 Hz, 1H), 7.55-7.58 (m, 1H), 7.73 (td, J =
7.5, 1.9 Hz, 1H), 7.83-7.88 (m, 1H) 6-(2-Methoxy-4-methylsulfon-
.sup.1H-NMR (500 MHz, CDCl.sub.3) yloxyphenyl)-5-(2-methoxy-5-
.delta. 1.05 (s, 3H), 1.27 (s, 3H), nitrophenoxymethyl)-2,2,4- 2.27
(s, 3H), 3.15 (s, 3H), trimethyl-1,2-dihydroquino- 3.78 (s, 3H),
3.84 (s, 3H), 4.78 line (Compound No. 4-17) (d, J = 12.2 Hz, 1H),
5.35 ##STR00171## (d, J = 12.2 Hz, 1H), 5.47 (s, 1H), 6.56 (d, J =
8.2 Hz, 1H), 6.78 (d, J = 9.1 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H),
6.85 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.0, 2.4 Hz, 1H), 7.27 (d,
J = 2.7 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 9.1, 2.7
Hz, 1H) 5-(2-Methoxy-5-nitrophenoxy- .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) methyl)-6-(2-methoxy-4-prop- .delta. 0.99 (t, J = 7.3
Hz, 3H), ylsulfonyloxyphenyl)-2,2,4- 1.06 (s, 3H), 1.18 (s, 3H),
1.81 trimethyl-1,2-dihydroquino- (tq, J = 7.6, 7.3 Hz, 2H), line
(Compound No. 4-18) 2.14 (s, 3H), 3.44 (t, J = 7.6 ##STR00172## Hz,
2H), 3.71 (s, 3H), 3.82 (s, 3H), 4.63 (d, J = 11.9 Hz, 1H), 5.23
(d, J = 11.9 Hz, 1H), 5.41 (s, 1H), 6.05 (s, 1H), 6.62 (d, J = 8.2
Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.83 (dd, J = 8.2, 2.4 Hz, 1H),
6.92 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 7.19 (d, J =
8.2 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.81 (dd, J = 9.1, 2.7 Hz,
1H) 6-(4-Cyclopropylsulfonyloxy- .sup.1H-NMR (400 MHz, CDCl.sub.3)
2-methoxyphenyl)-5-(2-meth- .delta. 1.04 (s, 3H), 1.08-1.12 (m,
oxy-5-nitrophenoxymethyl)- 2H), 1.23-1.26 (m, 2H), 1.27
2,2,4-trimethyl-1,2-dihydro- (s, 3H), 2.27 (s, 3H), 2.55-2.61
quinoline (Compound No. 4-19) (m, 1H), 3.77 (s, 3H), 3.84
##STR00173## (s, 3H), 4.77 (d, J = 12.4 Hz, 1H), 5.35 (d, J = 12.4
Hz, 1H), 5.47 (s, 1H), 6.07 (s, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.78
(d, J = 9.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 2.2 Hz,
1H), 6.90 (dd, J = 8.3, 2.2 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.30
(d, J = 8.3 Hz, 1H), 7.78 (dd, J = 9.0, 2.7 Hz, 1H)
6-(4-Isopropylsulfonyloxy-2- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methoxyphenyl)-5-(2-methoxy- .delta. 1.06 (s, 3H), 1.18 (s, 3H),
5-nitrophenoxymethyl)-2,2,4- 1.39 (d, J = 6.7 Hz, 6H), 2.14
trimethyl-1,2-dihydro- (s, 3H), 3.62-3.67 (m, 1H), quinoline
(Compound No. 4-20) 3.71 (s, 3H), 3.82 (s, 3H), 4.61 ##STR00174##
(d, J = 11.9 Hz, 1H), 5.23 (d, J = 11.9 Hz, 1H), 5.41 (s, 1H), 6.05
(s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.82
(dd, J = 8.2, 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 7.08 (d, J =
9.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H),
7.81 (dd, J = 9.1, 2.7 Hz, 1H) 6-(4-Isobutylsulfonyloxy-2-
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) methoxyphenyl)-5-(2-methoxy-
.delta. 1.03 (d, J = 6.6 Hz, 6H), 5-nitrophenoxymethyl)-2,2,4- 1.06
(s, 3H), 1.18 (s, 3H), 2.14 trimethyl-1,2-dihydroquino- (s, 3H),
2.18-2.25 (m, 1H), line (Compound No. 4-21) 3.39 (d, J = 6.6 Hz,
2H), 3.71 ##STR00175## (s, 3H), 3.82 (s, 3H), 4.62 (d, J = 12.1 Hz,
1H), 5.23 (d, J = 12.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.62
(d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.83 (dd, J = 8.3,
2.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H),
7.19 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.81 (dd, J =
9.0, 2.7 Hz, 1H) 5-(2-Methoxy-5-nitrophenoxy- .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) methyl)-6-[2-methoxy-4-(3,3,3- .delta. 1.06 (s, 3H),
1.18 (s, 3H), trifluoropropylsulfonyl- 2.14 (s, 3H), 2.92-2.95 (m,
2H), oxy)phenyl]-2,2,4-trimethyl- 3.71 (s, 3H), 3.78-3.82
1,2-dihydroquinoline (Compound (m, 2H), 3.82 (s, 3H), 4.62 No.
4-22) (d, J = 11.9 Hz, 1H), 5.23 (d, ##STR00176## J = 11.9 Hz, 1H),
5.41 (s, 1H), 6.06 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.75 (d, J =
8.2 Hz, 1H), 6.89 (dd, J = 8.3, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz,
1H), 7.07 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.32 (d, J
= 2.6 Hz, 1H), 7.81 (dd, J = 9.1, 2.6 Hz, 1H)
6-(4-Ethylsulfonyloxy-2-meth- .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
oxyphenyl)-5-(2-methyl-5- .delta. 0.93 (s, 3H), 1.18 (s, 3H),
nitrophenoxymethyl)-2,2,4- 1.35 (t, J = 7.3 Hz, 3H), 2.13
trimethyl-1,2-dihydroquinoline (s, 3H), 2.17 (s, 3H), 3.51
(Compound No. 4-23) (q, J = 7.3 Hz, 2H), 3.76 (s, ##STR00177## 3H),
4.76 (d, J = 12.6 Hz, 1H), 5.29 (d, J = 12.6 Hz, 1H), 5.41 (s, 1H),
6.07 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H),
6.95 (dd, J = 8.2, 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 7.15 (d,
J = 2.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz,
1H), 7.64 (dd, J = 8.2, 2.1 Hz, 1H)
6-(4-Butylsulfonyloxy-2-meth- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
oxyphenyl)-5-(2-methyl-5- .delta. 0.89 (t, J = 7.3 Hz, 3H),
nitrophenoxymethyl)-2,2,4- 0.93 (s, 3H), 1.18 (s, 3H), 1.38-
trimethyl-1,2-dihydroquinoline 1.45 (m, 2H), 1.75-1.81 (Compound
No. 4-24) (m, 2H), 2.13 (s, 3H), 2.17 ##STR00178## (s, 3H),
3.48-3.52 (m, 2H), 3.76 (s, 3H), 4.76 (d, J = 12.5 Hz, 1H), 5.29
(d, J = 12.5 Hz, 1H), 5.41 (s, 1H), 6.07 (s, 1H), 6.62 (d, J = 8.2
Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.3 Hz, 1H),
6.99 (d, J = 2.3 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.31 (d, J =
8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 2.2 Hz,
1H) 6-(2-Methoxy-4-propylsulfon- .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) yloxyphenyl)-5-(2-methyl-5- .delta. 0.93 (s, 3H),
1.01 (t, J = nitrophenoxymethyl)-2,2,4- 7.5 Hz, 3H), 1.18 (s, 3H),
1.80- trimethyl-1,2-dihydroquinoline 1.87 (m, 2H), 2.13 (s, 3H),
(Compound No. 4-25) 2.17 (s, 3H), 3.49 (t, J = 7.6 ##STR00179## Hz,
2H), 3.76 (s, 3H), 4.76 (d, J = 12.5 Hz, 1H), 5.29 (d, J = 12.5 Hz,
1H), 5.41 (s, 1H), 6.07 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.79 (d,
J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 2.4 Hz, 1H), 6.98 (d, J = 2.4
Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.33
(d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 2.2 Hz, 1H)
6-(4-Isopropylsulfonyloxy-2- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methoxyphenyl)-5-(2-methyl- .delta. 0.93 (s, 3H), 1.18 (s, 3H),
5-nitrophenoxymethyl)-2,2,4- 1.42 (d, J = 6.7 Hz, 6H), 2.13
trimethyl-1,2-dihydroquino- (s, 3H), 2.17 (s, 3H), 3.68- line
(Compound No. 4-26) 3.74 (m, 1H), 3.76 (s, 3H), 4.75 ##STR00180##
(d, J = 12.5 Hz, 1H), 5.28 (d, J = 12.5 Hz, 1H), 5.41 (s, 1H), 6.07
(s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.93
(dd, J = 8.2, 2.2 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 7.16 (d, J =
2.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H),
7.64 (dd, J = 8.2, 2.1 Hz, 1H) 6-(4-Cyclopropylsulfonyloxy-
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) 2-methoxyphenyl)-5-(5-fluoro-
.delta. 0.89-0.94 (m, 2H), 1.04-1.08 2-methylphenoxymethyl)- (m,
2H), 1.08 (s, 3H), 1.15 2,2,4-trimethyl-1,2-dihydro- (s, 3H), 2.01
(s, 3H), 2.07 quinoline (Compound No. 4-27) (s, 3H), 3.01 (tt, J =
7.9, 4.9 ##STR00181## Hz, 1H), 3.75 (s, 3H), 4.56 (d, J = 12.1 Hz,
1H), 5.04 (d, J = 12.1 Hz, 1H), 5.41 (s, 1H), 6.07 (s, 1H), 6.38
(dd, J = 11.3, 2.4 Hz, 1H), 6.53 (td, J = 8.6, 2.4 Hz, 1H), 6.64
(d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2,
2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 7.22 (d,
J = 8.2 Hz, 1H) 5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) methyl)-6-(4-isobutylsulfon- .delta. 1.06 (d, J = 7.0
Hz, 6H), yloxy-2-methoxyphenyl)-2,2,4- 1.07 (s, 3H), 1.15 (s, 3H),
2.00 trimethyl-1,2-dihydroquino- (s, 3H), 2.06 (s, 3H), 2.21- line
(Compound No. 4-28) 2.26 (m, 1H), 3.43 (d, J = 6.4 ##STR00182## Hz,
2H), 3.75 (s, 3H), 4.59 (d, J = 12.1 Hz, 1H), 5.05 (d, J = 12.1 Hz,
1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.36 (dd, J = 11.5, 2.6 Hz, 1H),
6.53 (td, J = 8.5, 2.6 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.77 (d,
J = 8.2 Hz, 1H), 6.92 (dd, J = 8.3, 2.2 Hz, 1H), 6.98 (d, J = 2.2
Hz, 1H), 7.01-7.05 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H)
6-(4-Cyclopentylsulfonyloxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
2-methoxyphenyl)-5-(5-fluoro- .delta. 1.07 (s, 3H), 1.15 (s, 3H),
2-methylphenoxymethyl)- 1.57-1.65 (m, 2H), 1.68-1.75
2,2,4-trimethyl-1,2-dihydro- (m, 2H), 1.95-2.02 (m, 2H), 2.01
quinoline (Compound No. 4-29) (s, 3H), 2.04-2.11 (m, 2H),
##STR00183## 2.06 (s, 3H), 3.75 (s, 3H), 3.94 (tt, J = 8.9, 6.7 Hz,
1H), 4.57 (d, J = 11.9 Hz, 1H), 5.05 (d, J = 11.9 Hz, 1H), 5.40 (s,
1H), 6.06 (s, 1H), 6.37 (dd, J = 11.3, 2.4 Hz, 1H), 6.53 (td, J =
8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz,
1H), 6.90 (dd, J = 8.2, 2.1 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H),
7.02- 7.05 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxy- .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
methyl)-6-[2-methoxy-4-(3,3,3- .delta. 1.07 (s, 3H), 1.15 (s, 3H),
trifluoroproprylsulfonyl- 2.00 (s, 3H), 2.06 (s, 3H),
oxy)phenyl]-2,2,4-trimethyl- 2.90-3.00 (m, 2H), 3.75 (s, 3H),
1,2-dihydroquinoline 3.83-3.87 (m, 2H), 4.59 (Compound No. 4-30)
(d, J = 12.1 Hz, 1H), 5.05 (d, ##STR00184## J = 12.1 Hz, 1H), 5.40
(s, 1H), 6.07 (s, 1H), 6.35 (dd, J = 11.5, 2.4 Hz, 1H), 6.52 (td, J
= 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz,
1H), 6.97 (dd, J = 8.2, 2.3 Hz, 1H), 7.01-7.05 (m, 1H), 7.06 (d, J
= 2.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H)
Example 5
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methoxycarbonyloxyphenyl-
)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 5-1)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg,
0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL),
triethylamine (23 .mu.L, 0.17 mmol) and methyl chlorocarbonate (6.8
.mu.L, 0.088 mmol) were added thereto, and then the mixture was
stirred at room temperature for 20 minutes. The reaction mixture
was purified by silica gel column chromatography (hexane-ethyl
acetate) to give the titled compound (28.0 mg) as a colorless
amorphous product. (Yield 99%)
TABLE-US-00021 ##STR00185## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H),
3.72 (s, 3H), 3.83 (s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d, J =
12.2 Hz, 1H), 5.39 (s, 1H), 6.04 (s, 1H), 6.35 (dd, J = 11.3, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 2.3 Hz, 1H), 6.98 (d,
J = 2.3 Hz, 1H), 7.02-7.05 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H)
Using any compounds among Reference Compounds No. 3-1, 3-3 and 3-4,
the following Compounds (No. 5-2.about.5-10) were obtained by a
method similar to that of Compound No. 5-1.
TABLE-US-00022 5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-
phenoxycarbonyloxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-2) ##STR00186## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H), 2.07 (s, 3H),
3.75 (s, 3H), 4.62 (d, J = 12.2 Hz, 1H), 5.08 (d, J = 12.2 Hz, 1H),
5.40 (s, 1H), 6.05 (s, 1H), 6.36 (dd, J = 11.3, 2.4 Hz, 1H), 6.52
(td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.79 (d, J =
8.2 Hz, 1H), 6.97 (dd, J = 8.2, 2.4 Hz, 1H), 7.02-7.05 (m, 1H),
7.14 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.34 (t, J =
7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H)
6-[4-(2-Chlorophenoxycarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-3) ##STR00187## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H),
3.76 (s, 3H), 4.61 (d, J = 11.9 Hz, 1H), 5.07 (d, J = 11.9 Hz, 1H),
5.40 (s, 1H), 6.06 (s, 1H), 6.37 (dd, J = 11.5, 2.4 Hz, 1H), 6.52
(td, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.79 (d, J =
8.2 Hz, 1H), 6.96 (dd, J = 8.3, 2.3 Hz, 1H), 7.01-7.05 (m, 1H),
7.10 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.39 (td, J =
7.9, 1.6 Hz, 1H), 7.48 (td, J = 7.9, 1.7 Hz, 1H), 7.61 (dd, J =
7.9, 1.6 Hz, 1H), 7.66 (dd, J = 7.9, 1.7 Hz, 1H)
6-[4-(4-Chlorophenoxycarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-4) ##STR00188## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H),
3.75 (s, 3H), 4.61 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H),
5.40 (s, 1H), 6.05 (s, 1H), 6.36 (dd, J = 11.3, 2.4 Hz, 1H), 6.52
(td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.1 Hz), 1H), 6.79 (d, J =
8.1 Hz, 1H), 6.97 (dd, J = 8.2, 2.4 Hz, 1H), 7.02-7.05 (m, 1H),
7.15 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.45 (d, J =
9.1 Hz, 2H), 7.55 (d, J = 9.1 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
methoxyphenoxycarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-5) ##STR00189## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H),
3.76 (s, 3H), 3.86 (s, 3H), 4.62 (d, J = 12.1 Hz, 1H), 5.07 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.36 (dd, J = 11.3, 2.4
Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.3 Hz, 1H), 7.01 (td,
J = 8.0, 1.4 Hz, 1H), 7.02-7.05 (m, 1H), 7.05 (d, J = 2.3 Hz, 1H),
7.20 (dd, J = 8.0, 1.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.31 (td,
J = 8.0, 1.6 Hz, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methoxyphenoxycarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-6) ##STR00190## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H),
3.75 (s, 3H), 3.77 (s, 3H), 4.61 (d, J = 12.1 Hz, 1H), 5.07 (d, J =
12.1 Hz, 1H), 5.40 (s, 1H), 6.05 (s, 1H), 6.36 (dd, J = 11.6, 2.4
Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.79 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.4 Hz, 1H), 7.00 (d,
J = 9.2 Hz, 2H), 7.02-7.05 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.23
(d, J = 8.2 Hz, 1H), 7.30 (d, J = 9.2 Hz, 2H)
6-(4-Benzyloxycarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-7) ##STR00191## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H),
3.72 (s, 3H), 4.61 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H),
5.27 (s, 2H), 5.39 (s, 1H), 6.04 (s, 1H), 6.35 (dd, J = 11.3, 2.4
Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H),
6.77 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.2, 2.3 Hz, 1H), 7.00 (d,
J = 2.3 Hz, 1H), 7.02-7.05 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H),
7.37-7.47 (m, 5H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2,2,2-
trichloroethoxycarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-8) ##STR00192## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.06 (s, 3H), 1.15 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H),
3.74 (s, 3H), 4.61 (d, J = 11.1 Hz, 1H), 5.06 (s, 2H), 5.07 (d, J =
11.1 Hz, 1H), 5.40 (s, 1H), 6.06 (s, 1H), 6.36 (dd, J = 11.5, 2.4
Hz, 1H), 6.53 (td, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 8.3, 2.2 Hz, 1H), 7.02-7.06
(m, 1H), 7.05 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H)
6-[4-(4-Chlorophenoxycarbonyloxy)-2-methoxyphenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-9) ##STR00193## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.05 (s, 3H), 1.18 (s, 3H), 2.14 (s, 3H), 3.71 (s, 3H),
3.81 (s, 3H), 4.65 (d, J = 11.9 Hz, 1H), 5.25 (d, J = 11.9 Hz, 1H),
5.40 (s, 1H), 6.03 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.76 (d, J =
8.2 Hz, 1H), 6.90 (dd, J = 8.2, 2.3 Hz, 1H), 7.08 (d, J = 9.1 Hz,
1H), 7.10 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.31 (d, J
= 2.7 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H),
7.81 (dd, J = 9.1, 2.7 Hz, 1H)
6-(2-Methoxy-4-methoxycarbonyloxyphenyl)-5-(2-methoxy-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 5-10) ##STR00194## 1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.04 (s, 3H), 1.18 (s, 3H), 2.14 (s, 3H), 3.68 (s, 3H),
3.81 (s, 3H), 3.82 (s, 3H), 4.65 (d, J = 12.2 Hz, 1H), 5.25 (d, J =
12.2 Hz, 1H), 5.40 (s, 1H), 6.02 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H),
6.75 (dd, J = 8.1, 2.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.93 (d,
J = 2.2 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 7.14 (d, J = 8.1 Hz,
1H), 7.31 (d, J = 2.7 Hz, 1H), 7.81 (dd, J = 9.1, 2.7 Hz, 1H)
Example 6
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-phenylaminocarbonyloxyph-
enyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-1)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg,
0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL),
triethylamine (19.3 .mu.L, 0.138 mmol) and phenyl isocyanate (9.5
.mu.L, 0.087 mmol) were added thereto, and then the mixture was
stirred at room temperature for 2 hours. The reaction mixture was
purified by silica gel column chromatography (hexane-ethyl acetate)
to give the titled compound (27.3 mg) as a colorless amorphous
product. (Yield 86%)
TABLE-US-00023 ##STR00195## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
3.76 (s, 3H), 3.88 (brs, 1H), 4.76 (d, J = 12.0 Hz, 1H), 5.12 (d, J
= 12.0 Hz, 1H), 5.46 (s, 1H), 6.20 (dd, J = 11.2, 2.4 Hz, 1H), 6.42
(td, J = 8.3, 2.4 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.82-6.84 (m,
2H), 6.90-6.95 (m, 3H), 7.11- 7.14 (m, 1H), 7.25-7.27 (m, 1H), 7.36
(t, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H)
6-[4-[N-(2-dimethylaminoethyl)-N-methylaminocarbonyloxy]-2-methoxyphenyl]--
5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-2)
A mixture of
5-(5-fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-tr-
imethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 26.0 mg,
0.0600 mmol), 1,1'-carbonyldiimidazole (31.4 mg, 0.194 mmol) and
4-dimethylaminopyridine (1.1 mg, 0.0090 mmol) was dissolved in
anhydrous tetrahydrofuran (0.6 mL), and then the mixture was
stirred at room temperature for 1 hour.
N,N,N'-trimethylethylenediamine (15 .mu.L, 0.12 mmol) was added
thereto, the mixture was stirred at room temperature for 1 hour,
and then the mixture was purified by silica gel column
chromatography (hexane-ethyl acetate) to give the titled compound
(10.0 mg) as a colorless amorphous product. (Yield 30%)
TABLE-US-00024 ##STR00196## .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.04 (s, 3H), 1.14 (s, 3H), 2.02 (s, 3H), 2.07 (s, 3H),
2.18 (s, 3H), 2.20 (m, 3H), 2.41-2.54 (m, 2H), 2.92- 3.04 (m, 3H),
3.30-3.37 (m, 2H), 3.71 (s, 3H), 4.62 (d, J = 12.1 Hz, 1H), 5.08
(d, J = 12.1 Hz, 1H), 5.39 (s, 1H), 6.01 (s, 1H), 6.34 (dd, J =
11.8, 2.2 Hz, 1H), 6.52 (td, J = 8.2, 2.2 Hz, 1H), 6.63 (d, J = 7.9
Hz, 1H), 6.68-6.72 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.81-6.83 (m,
1H), 7.02- 7.05 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H)
Using any compounds among Reference Compounds No. 3-1, 3-3 and 3-4,
the following Compounds (No. 6-3.about.6-41) were obtained by a
method similar to that of Compound No. 1-1, 6-1 or 6-2.
TABLE-US-00025
6-[4-(2-Chlorophenylaminocarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No.6-3) ##STR00197## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.13 (s, 3H), 1.23 (s, 3H), 2.08 (s, 3H), 2.16 (s, 3H),
3.77 (s, 3H), 3.88 (br s, 1H), 4.76 (d, J = 12.1 Hz, 1H), 5.12 (d,
J = 12.1 Hz, 1H), 5.46 (s, 1H), 6.20 (dd, J = 11.2, 2.5 Hz, 1H),
6.43 (td, J = 8.4, 2.5 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.84 (d,
J = 2.4 Hz, 1H), 6.85 (dd, J = 8.2, 2.4 Hz, 1H), 6.91 (d, J = 8.2
Hz, 1H), 6.92-6.96 (m, 1H), 7.03-7.08 (m, 1H), 7.28 (d, J = 8.2 Hz,
1H), 7.29-7.33 (m, 1H), 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 7.50 (br s,
1H), 8.21 (d, J = 7.1 Hz, 1H)
6-[4-(3-Chlorophenylaminocarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No.6-4) ##STR00198## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
3.76 (s, 3H), 3.88 (br s, 1H), 4.75 (d, J = 12.0 Hz, 1H), 5.12 (d,
J = 12.0 Hz, 1H), 5.46 (s, 1H), 6.20 (dd, J = 11.2, 2.4 Hz, 1H),
6.42 (td, J = 8.3, 2.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.81-6.83
(m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.92-6.95 (m, 1H), 7.09-7.11 (m,
1H), 7.25-7.32 (m, 4H), 7.58 (br s, 1H)
6-[4-(4-Chlorophenylaminocarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No.6-5) ##STR00199## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
3.76 (s, 3H), 3.87 (br s, 1H), 4.75 (d, J = 12.2 Hz, 1H), 5.11 (d,
J = 12.2 Hz, 1H), 5.46 (s, 1H), 6.20 (dd, J = 11.3, 2.4 Hz, 1H),
6.42 (td, J = 8.2, 2.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.81 (d,
J = 1.9 Hz, 1H), 6.82 (dd, J = 6.9, 1.9 Hz, 1H), 6.90 (d, J = 8.1
Hz, 1H), 6.92-6.95 (m, 1H), 7.25-7.27 (m, 2H), 7.32 (d, J = 8.7 Hz,
2H), 7.42 (d, J = 8.7 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-
propylaminocarbonyloxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-6) ##STR00200## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 0.99 (t, J = 7.3 Hz, 3H), 1.11 (s, 3H), 1.22 (s, 3H),
1.59-1.64 (m, 2H), 2.07 (s, 3H), 2.15 (s, 3H), 3.23-3.28 (m, 2H),
3.75 (s, 3H), 3.85 (br s, 1H), 4.75 (d, J = 12.0 Hz, 1H), 5.03 (t,
J = 5.9 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.44 (s, 1H), 6.19 (dd,
J = 11.2, 2.4 Hz, 1H), 6.41 (td, J = 8.2, 2.4 Hz, 1H), 6.58 (d, J =
8.1 Hz, 1H), 6.75- 6.77 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H),
6.90-6.94 (m, 1H), 7.22 (d, J = 8.8 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-pyridin-
3-ylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-7) ##STR00201## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.13 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
3.76 (s, 3H), 3.91 (br s, 1H), 4.75 (d, J = 12.1 Hz, 1H), 5.12 (d,
J = 12.1 Hz, 1H), 5.46 (s, 1H), 6.20 (dd, J = 11.0, 2.5 Hz, 1H),
6.43 (td, J = 8.3, 2.5 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.82 (d,
J = 2.3 Hz, 1H), 6.83 (dd, J = 8.1, 2.3 Hz, 1H), 6.90 (d, J = 8.2
Hz, 1H), 6.92-6.95 (m, 1H), 7.07 (br s, 1H), 7.27 (d, J = 8.1 Hz,
1H), 7.31 (dd, J = 7.5, 4.9 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 8.38
(dd, J = 4.9, 1.8 Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-dimethylaminophenylaminocarbonylox-
y- 2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound
No. 6-8) ##STR00202## .sup.1H-NMR (400 MHz, Solv. CDCl.sub.3)
.delta. 1.11 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
2.93 (s, 6H), 3.76 (s, 3H), 3.86 (br s, 1H), 4.76 (d, J = 12.2 Hz,
1H), 5.12 (d, J = 12.2 Hz, 1H), 5.45 (s, 1H), 6.20 (dd, J = 11.1,
2.4 Hz, 1H), 6.42 (td, J = 8.3, 2.4 Hz, 1H), 6.58 (d, J = 8.1 Hz,
1H), 6.73-6.75 (m, 3H), 6.81-6.83 (m, 2H), 6.90 (d, J = 8.1 Hz,
1H), 6.91-6.95 (m, 1H), 7.24-7.26 (m, 1H), 7.32 (d, J = 7.8 Hz, 2H)
6-(4-Benzylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-9) ##STR00203## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.11 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H),
3.75 (s, 3H), 3.87 (br s, 1H), 4.48 (d, J = 5.9 Hz, 2H), 4.75 (d, J
= 12.1 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.34 (t, J = 5.9 Hz,
1H), 5.45 (s, 1H), 6.19 (dd, J = 11.2, 2.4 Hz, 1H), 6.41 (td, J =
8.3, 2.4 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.78-6.79 (m, 2H), 6.90
(d, J = 8.2 Hz, 1H), 6.90-6.95 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H),
7.29- 7.38 (m, 5H)
6-(4-Cyclohexylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-10) ##STR00204## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.11 (s, 3H), 1.20-1.27 (m, 4H), 1.22 (s, 3H), 1.35- 1.43
(m, 2H), 1.74-1.76 (m, 2H), 2.02-2.07 (m, 2H), 2.07 (s, 3H), 2.15
(s, 3H), 3.57- 3.59 (m, 1H), 3.74 (s, 3H), 3.86 (br s, 1H), 4.75
(d, J = 11.9 Hz, 1H), 4.91 (d, J = 7.9 Hz, 1H), 5.11 (d, J = 11.9
Hz, 1H), 5.44 (s, 1H), 6.19 (dd, J = 11.2, 2.4 Hz, 1H), 6.41 (td, J
= 8.2, 2.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.75-6.77 (m, 2H),
6.89 (d, J = 8.1 Hz, 1H), 6.91-6.94 (m, 1H), 7.21 (d, J = 7.9 Hz,
1H) 5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(2-
methoxyphenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinolin-
e (Compound No. 6-11) ##STR00205## .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16
(s, 3H), 3.76 (s, 3H), 3.85 (br s, 1H), 3.92 (s, 3H), 4.76 (d, J =
12.2 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 5.45 (s, 1H), 6.20 (dd, J
= 11.3, 2.4 Hz, 1H), 6.42 (td, J = 8.2, 2.4 Hz, 1H), 6.59 (d, J =
7.9 Hz, 1H), 6.83-6.85 (m, 2H), 6.90- 6.95 (m, 2H), 6.91 (d, J =
7.9 Hz, 1H), 6.99 (td, J = 7.8, 1.3 Hz, 1H), 7.05 (td, J = 7.8, 1.6
Hz, 1H), 7.25-7.27 (m, 1H), 7.60 (br s, 1H), 8.12 (br s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(3-
methoxyphenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinolin-
e (Compound No. 6-12) ##STR00206## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16
(s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.86 (br s, 1H), 4.75 (d, J =
12.0 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.45 (s, 1H), 6.20 (dd, J
= 11.1, 2.5 Hz, 1H), 6.42 (td, J = 8.3, 2.5 Hz, 1H), 6.59 (d, J =
8.1 Hz, 1H), 6.68 (dd, J = 7.9, 2.1 Hz, 1H), 6.81-6.84 (m, 2H),
6.90 (d, J = 8.3 Hz, 1H), 6.91-6.95 (m, 3H), 7.22-7.28 (m, 3H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methoxyphenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinolin-
e (Compound No. 6-13) ##STR00207## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16
(s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.86 (br s, 1H), 4.75 (d, J =
12.0 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.45 (s, 1H), 6.20 (dd, J
= 11.2, 2.4 Hz, 1H), 6.42 (td, J = 8.3, 2.4 Hz, 1H), 6.59 (d, J =
8.1 Hz, 1H), 6.81-6.83 (m, 3H), 6.88-6.95 (m, 3H), 6.91 (d, J = 8.1
Hz, 1H), 7.24-7.27 (m, 1H), 7.38 (d, J = 8.3 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methoxycarbonylphenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 6-14) ##STR00208## .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.08 (s, 3H),
2.16 (s, 3H), 3.77 (s, 3H), 3.87 (br s, 1H), 3.91 (s, 3H), 4.75 (d,
J = 12.1 Hz, 1H), 5.12 (d, J = 12.1 Hz, 1H), 5.46 (s, 1H), 6.20
(dd, J = 11.3, 2.4 Hz, 1H), 6.43 (td, J = 8.3, 2.4 Hz, 1H), 6.59
(d, J = 8.1 Hz, 1H), 6.82 (d, J = 1.9 Hz, 1H), 6.83 (dd, J = 7.1,
1.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.92-6.96 (m, 1H), 7.12 (br
s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 8.05
(d, J = 8.8 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(4-
methylphenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-15) ##STR00209## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.12 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
2.33 (s, 3H), 3.76 (s, 3H), 3.89 (br s, 1H), 4.76 (d, J = 12.1 Hz,
1H), 5.12 (d, J = 12.1 Hz, 1H), 5.45 (s, 1H), 6.20 (dd, J = 11.0,
2.4 Hz, 1H), 6.42 (td, J = 8.4, 2.4 Hz, 1H), 6.59 (d, J = 7.9 Hz,
1H), 6.82-6.83 (m, 2H), 6.87 (br s, 1H), 6.90-6.95 (m, 2H), 7.15
(d, J = 7.9 Hz 2H), 7.25 (d, J = 7.0 Hz, 1H), 7.35 (d, J = 7.9 Hz,
2H) 6-(4-Dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-16) ##STR00210## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.11 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H),
3.03 (s, 3H), 3.12 (s, 3H), 3.75 (s, 3H), 3.92 (br s, 1H), 4.75 (d,
J = 12.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.45 (s, 1H), 6.19
(dd, J = 11.1, 2.5 Hz, 1H), 6.41 (td, J = 8.3, 2.5 Hz, 1H), 6.60
(br s, 1H), 6.75 (br s, 2H), 6.89-6.94 (m, 2H), 7.23 (d, J = 8.1
Hz, 1H) 6-[4-(4-Cyanophenylaminocarbonyloxy)-2-methoxyphenyl]-5-
(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-17) ##STR00211## .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 1.13 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H),
3.76 (s, 3H), 3.91 (br s, 1H), 4.74 (d, J = 11.9 Hz, 1H), 5.11 (d,
J = 11.9 Hz, 1H), 5.46 (s, 1H), 6.19 (dd, J = 11.2, 2.5 Hz, 1H),
6.43 (td, J = 8.2, 2.5 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.81-6.83
(m, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.92-6.95 (m, 1H), 7.16 (br s,
1H), 7.28 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.65 (d, J
= 8.9 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(morpholin-
4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-18) ##STR00212## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.14 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 3.42 (br s, 2H), 3.58 (br s, 2H), 3.65 (t, J = 4.8
Hz, 4H), 3.71 (s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.2
Hz, 1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.34 (dd, J = 11.5, 2.4 Hz,
1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.74
(dd, J = 8.1, 2.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.86 (d, J =
2.3 Hz, 1H), 7.01-7.05 (m, 1H), 7.15 (d, J = 8.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(4-methylpiperazin-
1-ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-19) ##STR00213## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H),
2.07 (s, 3H), 2.22 (s, 3H), 2.33-2.38 (m, 4H), 3.43 (br s, 2H),
3.58 (br s, 2H), 3.71 (s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.07 (d,
J = 12.2 Hz, 1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.34 (dd, J = 11.3,
2.4 Hz, 1H), 6.52 (td, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.2 Hz,
1H), 6.72 (dd, J = 8.1, 2.1 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.85
(d, J = 2.1 Hz, 1H), 7.02- 7.05 (m, 1H), 7.15 (d, J = 8.1 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(piperidin-
1-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-20) ##STR00214## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.14 (s, 3H), 1.55 (br s, 6H),
2.02 (s, 3H), 2.07 (s, 3H), 3.41 (br s, 2H), 3.55 (br s, 2H), 3.71
(s, 3H), 4.61 (d, J = 12.2 Hz, 1H), 5.08 (d, J = 12.2 Hz, 1H), 5.39
(s, 1H), 6.02 (s, 1H), 6.34 (dd, J = 11.2, 2.4 Hz, 1H), 6.52 (td, J
= 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.2,
2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H),
7.01-7.05 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H)
6-(4-Isopropylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-21) ##STR00215## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.03 (s, 3H), 1.13 (d, J = 6.6 Hz, 6H), 1.14
(s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 3.64-3.68 (m, 1H), 3.71 (s,
3H), 4.63 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 12.3 Hz, 1H), 5.39 (s,
1H), 6.02 (s, 1H), 6.32 (dd, J = 11.6, 2.4 Hz, 1H), 6.52 (td, J =
8.4, 2.4 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.69 (dd, J = 8.1, 2.2
Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H),
7.01-7.05 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.8 Hz,
1H) 6-(4-t-Butylaminocarbonyloxy-2-methoxyphenyl)-5-(5-fluoro-
2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-22) ##STR00216## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.03 (s, 3H), 1.14 (s, 3H), 1.29 (s, 9H),
2.01 (s, 3H), 2.07 (s, 3H), 3.72 (s, 3H), 4.63 (d, J = 12.3 Hz,
1H), 5.09 (d, J = 12.3 Hz, 1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.32
(dd, J = 11.5, 2.5 Hz, 1H), 6.52 (td, J = 8.4, 2.5 Hz, 1H), 6.62
(d, J = 8.2 Hz, 1H), 6.67 (dd, J = 8.1, 2.4 Hz, 1H), 6.77 (d, J =
8.2 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.13 (d,
J = 8.1 Hz, 1H), 7.56 (s, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(N-methyl-
N-phenylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-23) ##STR00217## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.03 (s, 3H), 1.14 (s, 3H), 2.01 (s, 3H),
2.06 (s, 3H), 3.35 (s, 3H), 3.72 (s, 3H), 4.61 (d, J = 12.2 Hz,
1H), 5.07 (d, J = 12.2 Hz, 1H), 5.38 (s, 1H), 6.03 (s, 1H), 6.32
(dd, J = 11.4, 2.4 Hz, 1H), 6.51 (td, J = 8.4, 2.4 Hz, 1H), 6.62
(d, J = 8.2 Hz, 1H), 6.73-6.96 (m, 2H), 6.77 (d, J = 8.2 Hz, 1H),
7.01- 7.05 (m, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.28 (t, J = 7.8 Hz,
1H), 7.42 (t, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[4-(4-hydroxypiperidin-
1-ylcarbonyloxy)-2-methoxyphenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-24) ##STR00218## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.04 (s, 3H), 1.14 (s, 3H), 1.40 (br s, 2H),
1.78 (br s, 2H), 2.02 (s, 3H), 2.07 (s, 3H), 3.14 (br s, 1H), 3.30-
3.33 (m, 1H), 3.71 (s, 3H), 3.71 (br s, 2H), 3.86 (br s, 1H), 4.61
(d, J = 12.5 Hz, 1H), 4.80 (d, J = 4.2 Hz, 1H), 5.08 (d, J = 12.5
Hz, 1H), 5.39 (s, 1H), 6.02 (s, 1H), 6.34 (dd, J = 11.4, 2.5 Hz,
1H), 6.52 (td, J = 8.5, 2.5 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.71
(dd, J = 8.2, 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.84 (d, J =
2.2 Hz, 1H), 7.01-7.05 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(thiomorpholin-
4-ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-25) ##STR00219## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.05 (s, 3H), 1.15 (s, 3H), 2.02 (s, 3H),
2.07 (s, 3H), 2.67-2.76 (m, 4H), 3.65- 3.73 (m, 2H), 3.72 (s, 3H),
3.81-3.87 (m, 2H), 4.61 (d, J = 12.2 Hz, 1H), 5.08 (d, J = 12.2 Hz,
1H), 5.39 (s, 1H), 6.03 (s, 1H), 6.34 (dd, J = 11.5, 2.5 Hz, 1H),
6.53 (td, J = 8.4, 2.5 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.74 (dd,
J = 8.2, 2.3 Hz, 1H), 6.78 (dd, J = 8.3 Hz, 1H), 6.88 (d, J = 2.3
Hz, 1H), 7.02-7.05 (m, 1H), 7.16 (d, J = 8.2 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(N-methyl-
N-propylaminocarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-26) ##STR00220## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 0.88-1.01 (m, 3H), 1.11 (s, 3H), 1.22 (s, 3H), 1.64- 1.73
(m, 2H), 2.07 (s, 3H), 2.15 (s, 3H), 3.01-3.09 (m, 3H), 3.32-3.42
(m, 2H), 3.75 (s, 3H), 4.75 (d, J = 12.1 Hz, 1H), 5.11 (d, J = 12.1
Hz, 1H), 5.44 (s, 1H), 6.19 (dd, J = 11.1, 2.3 Hz, 1H), 6.41 (td, J
= 8.3, 2.3 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 6.72- 6.77 (m, 2H),
6.89-6.94 (m, 2H), 7.23 (d, J = 8.6 Hz, 1H)
5-(5-Fluoro-2-methylphenoxymethyl)-6-[2-methoxy-4-(piperazin-1-
ylcarbonyloxy)phenyl]-2,2,4-trimethyl-1,2-dihydroquinoline
monohydrochloride (Compound No. 6-27) ##STR00221## .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 1.09 (s, 3H), 1.20 (s, 3H), 2.01 (s,
3H), 2.09 (s, 3H), 3.19 (br s, 4H), 3.67 (br s, 2H), 3.73 (s, 3H),
3.82 (br s, 2H), 4.62-5.51 (br s, 1H), 4.63 (d, J = 12.2 Hz, 1H),
5.10 (d, J = 12.2 Hz, 1H), 5.51 (s, 1H), 6.34 (dd, J = 11.5, 2.2
Hz, 1H), 6.54 (td, J = 8.4, 2.4 Hz, 1H), 6.79 (dd, J = 8.2, 2.2 Hz,
1H), 6.77-6.91 (m, 2H), 6.91 (dd, J = 2.2 Hz, 1H), 7.02-7.06 (m,
1H), 7.19 (d, J = 8.2 Hz, 1H), 9.30 (br s, 1H), 9.37 (br s, 1H)
6-[2-Methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-
methoxy-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-28) ##STR00222## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.03 (s, 3H), 1.18 (s, 3H), 2.14 (s, 3H),
3.41-3.64 (m, 8H), 3.68 (s, 3H), 3.82 (s, 3H), 4.66 (d, J = 11.9
Hz, 1H), 5.25 (d, J = 11.9 Hz, 1H), 5.39 (s, 1H), 6.01 (s, 1H),
6.61 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.2, 2.3 Hz, 1H), 6.75 (d,
J = 8.2 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 9.0 Hz,
1H), 7.12 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.81 (dd,
J = 9.0, 2.7 Hz, 1H)
6-[4-[N-(2-Dimethylaminoethyl)-N-methylaminocarbonyloxy]-
2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-29)
##STR00223## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.02 (s,
3H), 1.18 (s, 3H), 2.14 (s, 3H), 2.17 (s, 6H), 2.32-2.68 (m, 2H),
2.90, 3.02 (s, 3H), 3.31-3.45 (m, 2H), 3.68 (s, 3H), 3.82 (s, 3H),
4.66 (d, J = 12.1 Hz, 1H), 5.26 (d, J = 12.1 Hz, 1H), 5.39 (s, 1H),
6.01 (s, 1H), 6.60-6.65 (m, 1H), 6.61 (d, J = 8.3 Hz, 1H),
6.74-6.78 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 7.07-7.12 (m, 1H),
7.08 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.80 (dd, J =
8.9, 2.7 Hz, 1H)
6-[2-Methoxy-4-(morpholin-4-ylcarbonyloxy)phenyl]-5-(2-
methyl-5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-30) ##STR00224## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.89 (s, 3H), 1.18 (s, 3H), 2.12 (s, 3H),
2.18 (s, 3H), 3.38-3.48 (m, 2H), 3.51- 3.63 (m, 2H), 3.63-3.67 (m,
4H), 3.73 (s, 3H), 4.77 (d, J = 12.5 Hz, 1H), 5.31 (d, J = 12.5 Hz,
1H), 5.40 (s, 1H), 6.02 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.77
(dd, J = 8.2, 2.0 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.87 (d, J =
2.0 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H),
7.33 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 2.1 Hz, 1H)
6-(4-Dimethylaminocarbonyloxy-2-methoxyphenyl)-5-(2-methyl-
5-nitrophenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline
(Compound No. 6-31) ##STR00225## .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.89 (s, 3H), 1.18 (s, 3H), 2.12 (s, 3H),
2.18 (s, 3H), 2.92 (s, 3H), 3.05 (s, 3H), 3.73 (s, 3H), 4.78 (d, J
= 12.5 Hz, 1H), 5.31 (d, J = 12.5 Hz, 1H), 5.39 (s, 1H), 6.02 (s,
1H), 6.62 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 8.2, 2.3 Hz, 1H), 6.79
(d, J = 8.2 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 2.1 Hz,
1H), 7.24 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.63 (dd,
J = 8.2, 2.1 Hz, 1H)
6-[4-[N-(2-Dimethylaminoethyl)-N-ethylaminocarbonyloxy]-
2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-32)
##STR00226## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.99 (s,
3H), 1.21-1.28 (m, 3H), 1.25 (s, 3H), 2.26 (s, 3H), 2.29 (s, 6H),
2.52- 2.57 (m, 2H), 3.41-3.50 (m, 4H), 3.76 (s, 3H), 3.79 (s, 1H),
3.83 (s, 3H), 4.86 (d, J = 12.7 Hz, 1H), 5.38 (d, J = 12.7 Hz, 1H),
5.44 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.73- 6.75 (m, 1H), 6.75
(d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.1 Hz,
1H), 7.26-7.28 (m, 1H), 7.28 (d, J = 2.6 Hz, 1H), 7.76 (dd, J =
8.9, 2.6 Hz, 1H)
6-[4-[N-(2-Dimethylaminoethyl)-N-methylaminocarbonyloxy]-
2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-33)
##STR00227## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.00 (s,
3H), 1.05 (t, J = 7.2 Hz, 6H), 1.26 (s, 3H), 2.26 (s, 3H), 2.58 (q,
J = 7.2 Hz, 4H), 2.66-2.71 (m, 2H), 3.04, 3.13 (s, 3H), 3.41- 3.50
(m, 2H), 3.75 (s, 3H), 3.83 (s, 3H), 4.85-4.89 (m, 1H), 5.37-5.40
(m, 1H), 5.44 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.72-6.75 (m, 1H),
6.72 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.87 (d, J =
8.1 Hz, 1H), 7.25-7.29 (m, 2H), 7.76 (dd, J = 8.9, 2.7 Hz, 1H)
6-[4-[N-(3-Dimethylaminopropyl)-N-methylaminocarbonyloxy]-
2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-34)
##STR00228## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.00 (s,
3H), 1.26 (s, 3H), 1.78-1.85 (m, 2H), 2.24 (s, 6H), 2.26 (s, 3H),
2.31- 2.36 (m, 2H), 3.02, 3.09 (s, 3H), 3.38-3.48 (m, 2H), 3.75 (s,
3H), 3.80 (s, 1H), 3.83 (s, 3H), 4.87 (d, J = 12.4 Hz, 1H), 5.38
(d, J = 12.4 Hz, 1H), 5.44 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H),
6.71-6.75 (m, 2H), 6.76 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 8.2 Hz,
1H), 7.26-7.30 (m, 2H), 7.77 (dd, J = 9.1, 2.6 Hz, 1H)
6-[4-[N-(2-Dimethylaminoethyl)-N-methylaminocarbonyloxy]-
2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-35)
##STR00229## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.06 (t, J =
7.2 Hz, 6H), 1.11 (s, 3H), 1.22 (s, 3H), 2.07 (s, 3H), 2.15 (s,
3H), 2.59 (q, J = 7.2 Hz, 4H), 2.66- 2.73 (m, 2H), 3.05, 3.14 (s,
3H), 3.42-3.52 (m, 2H), 3.75 (s, 3H), 4.76 (d, J = 11.5 Hz, 1H),
5.11 (d, J = 11.5 Hz, 1H), 5.44 (s, 1H), 6.19 (dd, J = 11.2, 2.3
Hz, 1H), 6.41 (td, J = 8.3, 2.3 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H),
6.73-6.77 (m, 2H), 6.88-6.94 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H)
6-[4-[N-(3-Dimethylaminopropyl)-N-methylaminocarbonyloxy]-
2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-36)
##STR00230## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.11 (s,
3H), 1.22 (s, 3H), 1.77-1.88 (m, 2H), 2.07 (s, 3H), 2.15 (s, 3H),
2.25 (s, 6H), 2.32-2.39 (m, 2H), 3.03, 3.11 (s, 3H), 3.38-3.51 (m,
2H), 3.75 (s, 3H), 4.75 (d, J = 12.1 Hz, 1H), 5.11 (d, J = 12.1 Hz,
1H), 5.44 (s, 1H), 6.19 (dd, J = 11.2, 2.5 Hz, 1H), 6.41 (td, J =
8.2, 2.5 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.72-6.77 (m, 2H),
6.88-6.95 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H)
6-[4-[N-Benzyl-N-(2-dimethyl-aminoethyl)aminocarbonyloxy]-
2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-37)
##STR00231## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.13 (s,
3H), 1.25 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.85 (s, 6H),
3.13-3.23 (m, 2H), 3.77 (s, 3H), 3.81- 3.96 (m, 2H), 4.66-4.85 (m,
3H), 5.11 (d, J = 12.2 Hz, 1H), 5.47 (s, 1H), 6.18 (dd, J = 11.1,
2.4 Hz, 1H), 6.42 (td, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 7.8 Hz,
1H), 6.79 (dd, J = 8.1, 1.7 Hz, 1H), 6.88- 6.96 (m, 3H), 7.25 (d, J
= 8.1 Hz, 1H), 7.32-7.52 (m, 5H)
6-[4-[N-(2-Dimethylaminoethyl)-N-(pyridin-3-ylmethyl)aminocarbonyloxy]-
2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-
dihydroquinoline (Compound No. 6-38) ##STR00232## .sup.1H-NMR (500
MHz, CDCl.sub.3) .delta. 1.11 (s, 3H), 1.23 (s, 3H), 2.07 (s, 3H),
2.15 (s, 3H), 2.28 (s, 3H), 2.30-2.34 (m, 3H), 2.54-2.62 (m, 2H),
3.50-3.54 (m, 2H), 3.73-3.77 (m, 3H), 4.64 (s, 1H), 4.72- 4.77 (m,
2H), 5.08-5.13 (m, 1H), 5.44 (s, 1H), 6.17-6.21 (m, 1H), 6.41 (td,
J = 8.2, 2.4 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 6.71-6.78 (m, 2H),
6.86-6.95 (m, 2H), 7.22-7.35 (m, 2H), 7.72-7.76 (m, 1H), 8.56-8.65
(m, 2H) 6-[4-[N-Benzyl-N-(2-dimethylaminoethyl)aminocarbonyloxy]-
2-methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-39)
##STR00233## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.99 (s,
3H), 1.26 (s, 3H), 2.24 (s, 3H), 2.26 (s, 6H), 2.50-2.51 (m, 2H),
3.46 (t, J = 7.0 Hz, 2H), 3.74, 3.77 (s, 3H), 3.82, 3.83 (s, 3H),
4.61, 4.70 (s, 2H), 4.84- 4.89 (m, 1H), 5.36-5.41 (m, 1H), 5.44 (s,
1H), 6.55 (d, J = 7.6 Hz, 1H), 6.67-6.88 (m, 4H), 7.27-7.38 (m,
7H), 7.76 (d, J = 8.9 Hz, 1H)
6-[4-[N-(2-Dimethylaminoethyl)-N-(pyridin-3-ylmethyl)aminocarbonyloxy]-2-
methoxyphenyl]-5-(2-methoxy-5-nitrophenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-40)
##STR00234## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.00 (s,
3H), 1.26 (s, 3H), 2.25 (s, 6H), 2.26 (s, 3H), 2.52 (t, J = 6.7 Hz,
2H), 3.48 (t, J = 6.7 Hz, 2H), 3.74, 3.77 (s, 3H), 3.83 (s, 3H),
3.83-3.88 (m, 1H), 4.63, 4.72 (s, 2H), 4.83-4.88 (m, 1H), 5.36-5.40
(m, 1H), 5.45 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.67-6.88 (m, 3H),
6.76 (d, J = 9.2 Hz, 1H), 7.26- 7.31 (m, 3H), 7.72-7.77 (m, 1H),
7.76 (d, J = 8.9 Hz, 1H), 8.57-8.62 (m, 2H)
6-[4-[N-(2-Dimethylaminoethyl)-N-ethylaminocarbonyloxy]-
2-methoxyphenyl]-5-(5-fluoro-2-methylphenoxymethyl)-
2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 6-41)
##STR00235## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.10 (s,
3H), 1.22 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H), 2.07 (s, 3H), 2.15 (s,
3H), 2.30 (s, 6H), 2.52-2.59 (m, 2H), 3.40-3.52 (m, 4H), 3.75 (s,
3H), 4.76 (d, J = 11.9 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 5.44 (s,
1H), 6.19 (dd, J = 11.3, 2.4 Hz, 1H), 6.41 (td, J = 8.4, 2.4 Hz,
1H), 6.57 (d, J = 8.2 Hz, 1H), 6.74- 6.77 (m, 2H), 6.87-6.94 (m,
2H), 7.22 (d, J = 8.6 Hz, 1H)
PREPARATION EXAMPLES
Hereinafter, typical preparation examples of the present compound
are shown.
1) Tablet (in 150 mg)
TABLE-US-00026 Present compound 1 mg Lactose 100 mg Cornstarch 40
mg Carboxymethyl cellulose calcium 4.5 mg Hydroxypropyl cellulose 4
mg Magnesium stearate 0.5 mg
A tablet of the above-mentioned formulation is coated with 3 mg of
a coating agent (for example, a coating agent which is used
conventionally such as hydroxypropylmethyl cellulose, macrogol or a
silicone resin), whereby an objective tablet can be obtained. In
addition, a desired tablet can be obtained by appropriately
changing the kind and/or amount of the present compound and
additives.
2) Capsule (in 150 mg)
TABLE-US-00027 Present compound 5 mg Lactose 135 mg Carboxymethyl
cellulose calcium 4.5 mg Hydroxypropyl cellulose 4 mg Magnesium
stearate 1.5 mg
A desired capsule can be obtained by appropriately changing the
kind and/or amount of the present compound and additives.
3) Eye Drop (in 100 mL)
TABLE-US-00028 Present compound 100 mg Sodium chloride 900 mg
Polysorbate 80 500 mg Sodium hydroxide q.s. Hydrochloric acid q.s.
Sterile purified water q.s.
A desired eye drop can be obtained by appropriately changing the
kind and/or amount of the present compound and additives.
[Pharmacological Test]
1. Evaluation Test for Binding Activity to Glucocorticoid Receptor
(Hereinafter Referred to as "GR")
In order to evaluate a binding activity to GR, a receptor
competitor assay was carried out by a fluorescence polarization
method. In the assay, a GR competitor assay kit (manufactured by
Invitrogen, cat No. P2816) was used, and a procedure was carried
out according to the protocol attached to the kit. Hereinafter, the
specific method will be described.
(Preparation of Reagents)
GR screening buffer: A buffer containing 10 mM potassium phosphate
(pH 7.4), 20 mM sodium molybdate (Na.sub.2MoO.sub.4), 0.1 mM
ethylene diamine tetraacetic acid (EDTA), 5 mM dithiothreitol
(DTT), 0.1 mM stabilizing peptide and 2% dimethylsulfoxide was
prepared.
4.times.GS1 solution: Fluormone.TM. GS1, which is a fluorescent
glucocorticoid ligand, was diluted with GR screening buffer,
whereby a 4 nM solution was prepared.
4.times.GR solution: Recombinant human GR was diluted with GR
screening buffer, whereby a 16 nM solution was prepared.
(Preparation of Test Compound Solution)
After a test compound was dissolved in dimethylsulfoxide, the
resulting solution was diluted with GR screening buffer, whereby a
20 .mu.M test compound solution was prepared.
(Test Method and Measurement Method)
1) The test compound solution was added in an amount of 10 .mu.L
into each well of a 384-well plate, and then, 4.times.GS1 solution
and 4.times.GR solution were added in an amount of 5 .mu.L into
each well, respectively.
2) The plate was incubated in a dark place at room temperature for
2 to 4 hours.
3) By using a multimode plate reader, Analyst.TM. HT (manufactured
by LJL Biosystems), fluorescence polarization of each well was
measured. As the blank, a well containing GR screening buffer in
place of the test compound and 4.times.GS1 solution was used.
4) The same procedure as that in the above 1) to 3) was carried out
except that GR screening buffer was used in place of the test
compound solution, and the obtained result was taken as the
negative control.
5) The same procedure as that in the above 1) to 3) was carried out
except that 2 mM dexamethasone was used in place of the test
compound solution, and the obtained result was taken as the
positive control.
(Calculation Equation of GR Binding Ratio)
A GR binding ratio (%) was calculated from the following equation.
GR binding ratio (%)=100.times.[1-(fluorescence polarization of
test compound solution-fluorescence polarization of positive
control solution)/(fluorescence polarization of negative control
solution-fluorescence polarization of positive control solution)]
(Test Results and Discussion)
As an example of the test results, the GR binding ratios (%) of the
test compounds (Compound 1-1, Compound 1-2, Compound 1-6, Compound
1-7, Compound 1-8, Compound 1-11, Compound 1-12, Compound 1-13,
Compound 1-14, Compound 1-16, Compound 1-17, Compound 1-18,
Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-27,
Compound 1-31, Compound 1-33, Compound 1-34, Compound 1-35,
Compound 1-40, Compound 1-43, Compound 1-44, Compound 1-45,
Compound 1-50, Compound 1-51, Compound 1-52, Compound 1-53,
Compound 1-54, Compound 1-55, Compound 1-56, Compound 1-58,
Compound 1-59, Compound 1-60, Compound 1-62, Compound 1-63,
Compound 1-64, Compound 1-67, Compound 1-68, Compound 1-69,
Compound 1-70, Compound 1-71, Compound 1-72, Compound 1-78,
Compound 1-86, Compound 1-90, Compound 1-91, Compound 1-93,
Compound 1-94, Compound 1-95, Compound 1-98, Compound 1-101,
Compound 1-102, Compound 1-115, Compound 1-121, Compound 1-122,
Compound 1-125, Compound 3-1, Compound 4-11, Compound 4-12,
Compound 4-13, Compound 4-14, Compound 4-18, Compound 4-19,
Compound 4-20, Compound 4-23, Compound 4-25, Compound 4-26,
Compound 4-27, Compound 4-28, Compound 4-29, Compound 4-30,
Compound 5-5, Compound 6-3, Compound 6-12, Compound 6-13, Compound
6-14, Compound 6-16, Compound 6-17, Compound 6-18, Compound 6-21,
Compound 6-28, Compound 6-30, Compound 6-31, Compound 6-37,
Compound 6-38, Compound 6-41) are shown in Table I.
TABLE-US-00029 TABLE I GR Binding Test compound ratio (%) Compound
1-1 94 Compound 1-2 100 Compound 1-6 100 Compound 1-7 100 Compound
1-8 100 Compound 1-11 100 Compound 1-12 100 Compound 1-13 100
Compound 1-14 100 Compound 1-16 100 Compound 1-17 100 Compound 1-18
100 Compound 1-19 100 Compound 1-20 100 Compound 1-21 100 Compound
1-27 84 Compound 1-31 100 Compound 1-33 89 Compound 1-34 100
Compound 1-35 100 Compound 1-40 100 Compound 1-43 100 Compound 1-44
100 Compound 1-45 95 Compound 1-50 97 Compound 1-51 91 Compound
1-52 96 Compound 1-53 100 Compound 1-54 100 Compound 1-55 100
Compound 1-56 100 Compound 1-58 100 Compound 1-59 100 Compound 1-60
100 Compound 1-62 100 Compound 1-63 100 Compound 1-64 100 Compound
1-67 100 Compound 1-68 100 Compound 1-69 100 Compound 1-70 100
Compound 1-71 100 Compound 1-72 98 Compound 1-78 100 Compound 1-86
91 Compound 1-90 95 Compound 1-91 96 Compound 1-93 92 Compound 1-94
100 Compound 1-95 93 Compound 1-98 100 Compound 1-101 99 Compound
1-102 100 Compound 1-115 97 Compound 1-121 100 Compound 1-122 100
Compound 1-125 100 Compound 3-1 100 Compound 4-11 100 Compound 4-12
92 Compound 4-13 89 Compound 4-14 90 Compound 4-18 99 Compound 4-19
98 Compound 4-20 100 Compound 4-23 100 Compound 4-25 100 Compound
4-26 100 Compound 4-27 100 Compound 4-28 100 Compound 4-29 100
Compound 4-30 100 Compound 5-5 93 Compound 6-3 98 Compound 6-12 98
Compound 6-13 100 Compound 6-14 88 Compound 6-16 100 Compound 6-17
90 Compound 6-18 100 Compound 6-21 92 Compound 6-28 100 Compound
6-30 100 Compound 6-31 100 Compound 6-37 99 Compound 6-38 100
Compound 6-41 87
Incidentally, in the case where the GR binding ratio of the test
compound is 100% or more, the GR binding ratio is indicated by
100%.
As is apparent from Table I, the present compound showed an
excellent GR binding activity. Accordingly, the present compound
can be used as a GR modulator, and is useful for a preventive or
therapeutic agent particularly for GR-related diseases, that is,
metabolic disorders, inflammatory diseases, autoimmune diseases,
allergic diseases, central nervous system diseases, cardiovascular
diseases, homeostasis-related diseases, glaucoma and the like.
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